Fungicidal-2-alkoxy/haloalkoxy-1-(mono- or disubstituted)amino-4,4-disubstituted-2-imidazolin-5-ones

ABSTRACT

Fungicidal 2-imidazolin-5-ones and 2-imidazoline-5-thiones, processes for their preparation, fungicidal compositions containing them and methods of using them to treat or prevent fungal disease in crops.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 08/352,814, filed Dec. 1,1994, which is a continuation-in-part of earlier U.S. application Ser.No. 07/993,700, filed Dec. 21, 1992, now abandoned; International PatentApplication No. PCT/FR93/00647, filed Jun. 29, 1993 and designating theUnited States; U.S. application Ser. No. 08/156,647, filed Nov. 24,1993, now abandoned; and U.S. application Ser. No. 08/262,459, filedJun. 20, 1994 now abandoned; all of which are incorporated by referenceherein in their entireties and relied upon.

The present invention relates to novel fungicidal imidazolinone andimidazolinethione compounds for use in plant protection. It also relatesto the processes for the preparation of said compounds and to thecompounds which can optionally be used as intermediates in thepreparation process. It further relates to the use of these compounds asfungicides, to fungicidal compositions comprising these compounds and tomethods for combating fungal diseases in crops using these compounds.

One object of the present invention is to provide compounds showingimproved properties in the treatment of fungal diseases.

Another object of the present invention is to provide compounds showinga spectrum of use in the field of fungal diseases which is alsoimproved.

In a first major aspect of the present invention, it has been found thatthese objects can be achieved by virtue of compounds of the inventionwhich are 2-imidazolin-5-one and 2-imidazoline-5-thione derivatives ofthe general formula (I): ##STR1## wherein: W is a sulfur or oxygen atomor an S═O group;

A represents O or S;

n=0 or 1;

B represents NR₅ or O or S or CR₅ R₆ or SO₂ or C═O;

R₁ and R₂, which are identical or different, represent:

H, provided that one of the two groups is different from H;

an alkyl or haloalkyl radical having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, monoalkylaminoalkyl,alkenyl or alkynyl radical having 2 to 6 carbon atoms;

a dialkylaminoalkyl or cycloalkyl radical having 3 to 7 carbon atoms;

an aryl radical comprising phenyl, naphthyl, thienyl, furyl, pyridyl,benzothienyl, benzofuryl, quinolyl, isoquinolyl or methylenedioxyphenyl,optionally substituted by 1 to 3 groups chosen from R₇ ; or

an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical,the terms aryl and alkyl having the definitions given above;

or R₁ and R₂ can form, with the carbon to which they are bonded on thering, a carbocycle or a heterocycle having from 5 to 7 atoms, it beingpossible for these rings to be fused to a phenyl, optionally substitutedby 1 to 3 groups chosen from R₇ ;

R₃ represents:

an alkyl group having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, haloalkyl,cyanoalkyl, thiocyanatoalkyl, oxoalkyl, alkenyl or alkynyl group having2 to 6 carbon atoms;

a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamaoylalkyl grouphaving 3 to 6 carbon atoms;

a N,N-dialkylcarbamoylalkyl group having 4 to 8 carbon atoms; or

an arylalkyl group, the alkyl part being a radical having 1 to 6 carbonatoms and the aryl part being phenyl, naphthyl, thienyl, furyl orpyridyl, optionally substituted by 1 to 3 groups chosen from R₇ ;

R₄ represents:

a hydrogen atom (when n is equal to 1);

an alkyl group having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl,alkenyl or alkynyl group having 2 to 6 carbon atoms;

a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl grouphaving 3 to 6 carbon atoms;

a N,N-dialkylcarbamoylalkyl group having 4 to 8 carbon atoms;

an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolyl,isoquinolyl or methylenedioxyphenyl, optionally substituted by 1 to 3groups chosen from R₇ ;

an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical,the terms aryl and alkyl having the definitions given above;

an amino group disubstituted by two identical or different groups chosenfrom:

an alkyl radical having 1 to 6 carbon atoms;

an alkoxyalkyl, alkenyl or alkynyl radical having 3 to 6 carbon atoms;

a cycloalkyl radical having 3 to 7 carbon atoms;

an arylalkyl, such as defined above, phenyl or naphthyl radical,optionally substituted by 1 to 3 groups chosen from R₇ ; and

a thienylmethyl or furfuryl radical; or

a pyrrolidino, piperidino, morpholino or piperazino group, optionallysubstituted by aryl having 1 to 3 carbon atoms;

R₅ represents:

H, except when R₄ is H;

an alkyl, haloalkyl, alkylsulfonyl or haloalkylsulfonyl radical having 1to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, acyl, alkenyl, alkynyl, haloacyl,alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulfonyl orcyanoalkylsulfonyl radical having 2 to 6 carbon atoms;

an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl or cyanoalkoxycarbonylradical having 3 to 6 carbon atoms;

a formyl radical;

a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl oralkynylcarbonyl radical having 3 to 6 carbon atoms;

a cycloalkylcarbonyl radical having 4 to 8 carbon atoms;

a phenyl; arylalkylcarbonyl, especially phenylacetyl or phenylpropionyl;arylcarbonyl, especially benzoyl, optionally substituted by 1 to 3groups chosen from R₇ ; thienylcarbonyl; furylcarbonyl; pyridylcarbonyl;benzyloxycarbonyl; furfuryloxycarbonyl; tetrahydrofurfuryloxycarbonyl;thienylmethoxycarbonyl; pyridylmethoxycarbonyl; phenoxycarbonyl or(phenylthio)carbonyl, the phenyl being itself optionally substituted by1 to 3 groups chosen from R₇ ; (alkylthio)carbonyl;(haloalkylthio)carbonyl; (alkoxyalkylthio)carbonyl;(cyanoalkylthio)carbonyl; (benzylthio)carbonyl; (furfurylthio)carbonyl;(tetrahydrofurfurylthio)carbonyl; (thienylmethylthio)carbonyl;(pyridylmethylthio)carbonyl; or arylsulfonyl radical;

a carbamoyl radical, optionally mono- or disubstituted by:

an alkyl or haloalkyl group having 1 to 6 carbon atoms;

a cycloalkyl, alkenyl or alkynyl group having 3 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group having 2 to 6 carbonatoms; or

a phenyl, optionally substituted by 1 to 3 R₇ groups;

a sulfamoyl group, optionally mono- or disubstituted by:

an alkyl or haloalkyl group having 1 to 6 carbon atoms;

a cycloalkyl, alkenyl or alkynyl group having 3 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group having 2 to 6 carbonatoms; or

a phenyl, optionally substituted by 1 to 3 R₇ groups; or

an alkylthioalkylsulfonyl group having 3 to 8 carbon atoms or acycloalkylsulfonyl group having 3 to 7 carbon atoms;

R₆ represents:

a hydrogen atom;

a cyano group;

an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3to 7 carbon atoms;

an acyl or alkoxycarbonyl group having 2 to 6 carbon atoms; or

a benzoyl group, optionally substituted by 1 to 3 R₇ groups; and

R₇ represents:

a halogen atom;

an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio oralkylsulfonyl radical having 1 to 6 carbon atoms;

a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio oralkynylthio radical having 3 to 6 carbon atoms;

a nitro or cyano group;

an amino radical, optionally mono- or disubstituted by an alkyl or acylradical having 1 to 6 carbon atoms or an alkoxycarbonyl radical having 2to 6 carbon atoms; or

a phenyl, phenoxy or pyridyloxy radical, these radicals optionally beingsubstituted;

and the corresponding agriculturally acceptable salts.

Certain specific compounds of the formula (I), having the formula (Ia):##STR2## wherein W, R₁ to R₆ and n have the same meaning as in formula(I), are known. Denoted S-alkylated derivatives of5,5-diphenyl-2-thiohydantoin and of 5,5-diphenyldithiohydrantoin, thoseparticular compounds have been especially studied for theirpharmacological properties, as described in:

(a) Zejc, A., Dissertationes Pharmaceuticae et pharmacologicae, Warsaw,20 (5), 507-524 and 525-537 (1968);

(b) Lucka-Sobstel, B. and Zejc, A., Dissertationes Pharmaceuticae etpharmacologicae, 22 (1), 13-19 (1970); and

(c) Fetter, J., Harsanyi, K., Nyitrai, J. and Lempert, K., Acta Chemica(Budapest), 78 (3), 325-333 (1973).

No agricultural fungicidal activity has been previously described forthese compounds.

Other specific compounds of formula (I) have been described by (d)Bohme, Martin and Strahl in Archiv der Pharmazie, 313, 10-15 (1980).They are the three compounds of the formula: ##STR3## wherein R is H,CH₃ or phenyl. These compounds are thus included in the compounds offormula (Ib), which form part of the invention: ##STR4## wherein W andR₁ to R₅ have the same meaning as in formula (I) above.

In this first major aspect of the invention, the compounds which arepreferred for their better fungicidal activity and/or their ease ofsynthesis are:

(1) the compounds of formula (Ib);

(2) the compounds of formula (I), in particular those of formula (Ib),in which R₅ is a hydrogen atom;

(3) the compounds in which R₁ and R₂ are different from H;

(4) the compounds in which R₂ represents an alkyl group having 1 to 3carbon atoms;

(5) the compounds in which R₁ represents a phenyl ring, optionallysubstituted by R₇ ;

(6) the compounds in which R₃ represents an alkyl group having 1 to 3carbon atoms;

(7) the compounds in which R₄ represents a phenyl ring, optionallysubstituted by R₇ ; and

(8) the compounds in which R₃ represents a methyl group.

In a second major aspect of the present invention, the objects of theinvention noted hereinabove can be achieved by virtue of compounds ofthe invention which are 2-imidazolin-5-one and 2-imidazoline-5-thionederivatives of the general formula (I'): ##STR5## wherein: W is a sulfuror oxygen atom or an S═O group, as defined with formula (I) hereinabove;

n=0 or 1, as defined with formula (I) hereinabove;

A' represents NR₅ or O or S or CR₅ R₆ or SO₂ or C═O;

R₁ and R₂, which are identical or different, and which are as definedwith formula (I) above, represent:

H, provided that one of the two groups is different from H;

an alkyl or haloalkyl radical having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, monoalkylaminoalkyl,alkenyl or alkynyl radical having 2 to 6 carbon atoms;

a dialkylaminoalkyl or cycloalkyl radical having 3 to 7 carbon atoms;

an aryl radical comprising phenyl, naphthyl, thienyl, furyl, pyridyl,benzothienyl, benzofuryl, quinolyl, isoquinolyl or methylenedioxyphenyl,optionally substituted by 1 to 3 groups chosen from R₇ ; or

an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical,the terms aryl and alkyl having the definitions given above inconnection with formula (I');

or R₁ and R₂ can form, with the carbon to which they are bonded on thering, a carbocycle or a heterocycle having from 5 to 7 atoms, it beingpossible for these rings to be fused to a phenyl, optionally substitutedby 1 to 3 groups chosen from R₇ ;

R₃₀ represents:

a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, haloalkyl,cyanoalkyl, thiocyanatoalkyl, oxoalkyl, alkenyl or alkynyl group having2 to 6 carbon atoms;

a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl grouphaving 3 to 6 carbon atoms; or

an N,N-dialkylcarbamoylalkyl group having 4 to 8 carbon atoms;

R₄₀ represents:

a hydrogen atom (when n is equal to 1);

an alkyl group having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl,alkenyl or alkynyl group having 2 to 6 carbon atoms;

a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl grouphaving 3 to 6 carbon atoms;

an N,N-dialkylcarbamoylalkyl group having 4 to 8 carbon atoms;

an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyl,imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyrimidyl, pyridazinyl,pyrazinyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl ormethylenedioxyphenyl, optionally substituted by 1 to 3 groups chosenfrom R₇ ;

an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical,the terms aryl and alkyl having the definitions given above with respectto formula (I');

an amino group disubstituted by two identical or different groups chosenfrom:

an alkyl radical having 1 to 6 carbon atoms;

an alkoxyalkyl, alkenyl or alkynyl radical having 3 to 6 carbon atoms;

a cycloalkyl radical having 3 to 7 carbon atoms;

an arylalkyl, such as defined above with respect to formula (I'), phenylor naphthyl radical, optionally substituted by 1 to 3 groups chosen fromR₇ ; and

a thienylmethyl or furfuryl radical; or

a pyrrolidino, piperidino, morpholino or piperazino group, optionallysubstituted by alkyl having 1 to 3 carbon atoms;

R₅ is as defined with formula (I) above and represents:

H, except when R₄₀ is H;

an alkyl, haloalkyl, alkylsulfonyl or haloalkylsulfonyl radical having 1to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, acyl, alkenyl, alkynyl, haloacyl,alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulfonyl orcyanoalkylsulfonyl radical having 2 to 6 carbon atoms;

an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl or cyanoalkoxycarbonylradical having 3 to 6 carbon atoms;

a formyl radical;

a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl oralkynylcarbonyl radical having 3 to 6 carbon atoms;

a cycloalkylcarbonyl radical having 4 to 8 carbon atoms;

a phenyl; arylalkylcarbonyl, especially phenylacetyl or phenylpropionyl;arylcarbonyl, especially benzoyl, optionally substituted by 1 to 3groups chosen from R₇ ; thienylcarbonyl; furylcarbonyl; pyridylcarbonyl;benzyloxycarbonyl; furfuryloxycarbonyl; tetrahydrofurfuryloxycarbonyl;thienylmethoxycarbonyl; pyridylmethoxycarbonyl; phenoxycarbonyl or(phenylthio)carbonyl, the phenyl being itself optionally substituted by1 to 3 groups chosen from R₇ ; (alkylthio)carbonyl;(haloalkylthio)carbonyl; (alkoxyalkylthio)carbonyl;(cyanoalkylthio)carbonyl; (benzylthio)carbonyl; (furfurylthio)carbonyl;(tetrahydrofurfurylthio)carbonyl; (thienylmethylthio)carbonyl;(pyridylmethylthio)carbonyl; or arylsulfonyl radical; or

a carbamoyl radical, optionally mono- or disubstituted by:

an alkyl or haloalkyl group having 1 to 6 carbon atoms;

a cycloalkyl, alkenyl or alkynyl group having 3 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group having 2 to 6 carbonatoms; or

a phenyl, optionally substituted by 1 to 3 R₇ groups;

a sulfamoyl group, optionally mono- or disubstituted by:

an alkyl or haloalkyl group having 1 to 6 carbon atoms;

a cycloalkyl, alkenyl or alkynyl group having 3 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group having 2 to 6 carbonatoms; or

a phenyl, optionally substituted by 1 to 3 R₇ groups; or

an alkylthioalkylsulfonyl group having 3 to 8 carbon atoms or acycloalkylsulfonyl group having 3 to 7 carbon atoms;

R₆ is as defined with formula (I) above and represents:

a hydrogen atom;

a cyano group;

an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3to 7 carbon atoms;

an acyl or alkoxycarbonyl group having 2 to 6 carbon atoms; or

a benzoyl group, optionally substituted by 1 to 3 R₇ groups; and

R₇ is as defined with formula (I) above and represents:

a halogen atom;

an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio oralkylsulfonyl radical having 1 to 6 carbon atoms;

a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio oralkynylthio radical having 3 to 6 carbon atoms;

a nitro or cyano group;

an amino radical, optionally mono- or disubstituted by an alkyl or acylradical having 1 to 6 carbon atoms or an alkoxycarbonyl radical having 2to 6 carbon atoms; or

a phenyl, phenoxy or pyridyloxy radical, these radicals optionally beingsubstituted;

and the corresponding agriculturally acceptable salts and the opticallyactive isomers;

with the proviso that when n=0, R₄₀ is other than an optically activeresidue, deriving from an optically active primary amine or from anoptically active amino acid.

Certain compounds belonging to the family of the 2-imidazolin-5-ones ofgeneral formulae: ##STR6## are known for their herbicidal propertiesfrom the documents of European Patents 41623, 41624, 215738, 226947,261705, 303863, 433655 and 436483 and Patents U.S. Pat. No. 4,925,944,DE 3913757, GB 2167062, GB 2192877 and JP 3196570.

The imidazolinones of the formulae: ##STR7## have been described fortheir pharmaceutical properties by published applications WO 9114679, JP8055467 and DE 1176660 and 1258412, respectively. No agriculturalfungicidal activity has been described for compounds of formula (I').

The compounds of formula (I'a): ##STR8## wherein R₁, R₂, R₃₀, R₄₀, R₅and W are as defined with formula (I') are novel.

In this second major aspect of the invention, the compounds which arepreferred for their better fungicidal activity and/or for their ease ofsynthesis are:

(1) the compounds of formula (I'a);

(2) the compounds of formula (I'), in particular those of formula (I'a),in which R₅ is a hydrogen atom;

(3) the compounds in which R₁ and R₂ are other than H;

(4) the compounds in which R₂ represents an alkyl group having 1 to 3carbon atoms, preferably methyl;

(5) the compounds in which R₁ represents the phenyl ring, optionallysubstituted by R₇ ;

(6) the compounds in which R₃₀ represents a hydrogen atom or an alkylgroup having 1 to 3 carbon atoms, optionally substituted by one or morehalogens, methoxy or methylthio;

(7) the compounds in which R₄₀ represents the phenyl ring, optionallysubstituted by R₇ ; and

(8) the compounds of formula (I') in which W represents an oxygen atom.

In a third major aspect of the present invention, the objects of theinvention noted hereinabove can be achieved in whole or in part as aresult of compounds of the invention which are derivatives of2-alkoxy-2-imidazolin-5-ones of the general formula (I"): ##STR9##wherein: R₁₁ represents an aryl or heteroaryl radical having 1 or 2rings and from 5 to 10 ring atoms, from 0 to 3 of the ring atoms beingheteroatoms, which can be the same or different, selected from the groupconsisting of N, O and S, at least one ring being aromatic orheteroaromatic, said aryl or heteroaryl radical being optionallysubstituted by from 1 to 3 R₆₁ groups, which can be the same ordifferent (R₁₁ preferably being phenyl, naphthyl, thienyl, furyl,pyridyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl ormethylenedioxyphenyl, each of these radicals being optionallysubstituted by from 1 to 3 groups selected from among the meanings ofR₆₁);

R₂₁ represents an alkyl or haloalkyl radical having from 1 to 3 carbonatoms, the haloalkyl radical having 1 or more halogen atoms assubstituents;

or R₁₁ and R₂₁ form, together with the ring carbon atom to which theyare bonded, a carbocyclic or heteroacyclic ring having from 5 to 7 atomsand from 0 to 3 hetero ring atoms, which can be the same or different,selected from the group consisting of N, O and S, said ring beingoptionally fused to a benzene ring, the ring system being optionallysubstituted by from 1 to 3 R₆₁ groups, which can be the same ordifferent;

R₃₁ represents an alkyl or haloalkyl radical having from 1 to 3 carbonatoms, the haloalkyl radical being substituted by 1 or more halogenatoms;

R₄₁ represents an aryl or heteroaryl radical having 1 or 2 rings andfrom 5 to 10 ring atoms, from 0 to 3 of the ring atoms beingheteroatoms, which can be the same or different, selected from the groupconsisting of N, O and S, at least one ring being aromatic orheteroaromatic, said aryl or heteroaryl radical being optionallysubstituted by from 1 to 3 R₆₁ groups, which can be the same ordifferent (R₄₁ preferably being phenyl, naphthyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolinyl,isoquinolinyl or methylenedioxyphenyl, each of these radicals beingoptionally substituted by from 1 to 3 groups selected from among themeanings of R₆₁);

R₅₁ represents hydrogen, formyl, acyl having from 2 to 6 carbon atoms,aroyl, alkoxycarbonyl having from 2 to 6 carbon atoms, aryloxycarbonyl,alkylsulfonyl having from 1 to 6 carbon atoms or arylsulfonyl, the arylportion of the aroyl, aryloxycarbonyl and arylsulfonyl radicals havingfrom 6 to 10 carbon atoms and being optionally substituted by from 1 to3 R₆₁ groups, which can be the same or different; and

R₆₁ represents:

a halogen atoms;

an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy,alkylthio, haloalkylthio, cyanoalkylthio or alkylsulfonyl radical havingfrom 1 to 6 carbon atoms, the haloalkyl, haloalkoxy and haloalkylthioradicals bearing 1 or more halogen atoms as substituents;

a cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy,alkenylthio or alkynylthio radical having from 3 to 6 carbon atoms, thehalocycloalkyl radical bearing 1 or more halogen atoms as substituents;

a nitro, cyano or thiocyanato group;

an amino radical optionally mono- or disubstituted by an alkyl or acylradical having from 1 to 6 carbon atoms or an alkoxycarbonyl radicalhaving from 2 to 6 carbon atoms; or

a phenyl, phenoxy, phenylthio, phenylsulfonyl or pyridyloxy radical,each of which can be optionally substituted by one or more of thefollowing groups:

a halogen atom;

an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio or alkylsulfonyl radical having from 1 to 6 carbon atoms,the haloalkyl, haloalkoxy and haloalkylthio radicals bearing 1 or morehalogen atoms as substituents;

a cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy,alkenylthio or alkynylthio radical having from 3 to 6 carbon atoms, thehalocycloalkyl radical bearing 1 or more halogen atoms as substituents;

a nitro, cyano or thiocyanato group;

an amino radical optionally mono- or disubstituted by an alkyl or acylradical having from 1 to 6 carbon atoms or an alkoxycarbonyl radicalhaving from 2 to 6 carbon atoms; or

a phenyl, phenoxy, phenylthio, phenylsulfonyl or pyridyloxy radical;

and the corresponding agriculturally acceptable salts.

Preferred compounds of this third major aspect of the invention have theformula: ##STR10## wherein R₂₁ to R₆₁ have the same meanings as aboveand n" is 0, 1, 2 or 3.

R₄₁ preferably represents phenyl, substituted phenyl, pyridyl orsubstituted pyridyl.

R₅₁ preferably represents hydrogen or acyl (e.g. acetyl).

In a fourth major aspect of the present invention, it has been foundthat the objects of the invention noted hereinabove can be accomplishedby means of fungicidal optically active 2-imidazolin-5-one and2-imidazoline-5-thione derivatives. The corresponding racemic compoundsare compounds of formulae (I), (I') and (II") hereinabove, which aredescribed in earlier copending patent U.S. Ser. No. 07/993,700 filedDec. 21, 1992 (corresponding to European Patent Publication No. EP0551048, published Jul. 14, 1993), in earlier copending parent U.S. Ser.No. 08/156,647, filed Nov. 24, 1993 (corresponding to European PatentPublication No. EP 0599749, published Jun. 1, 1994), and in earliercopending parent International Application No. PCT/FR93/00647, filedJun. 29, 1993 (published as International PCT Publication No. WO94/01410, on Jan. 20, 1994); optically active isomers are described inearlier copending parent International Application No. PCT/FR93/00647and most especially in earlier copending parent U.S. Ser. No.08/262,459, filed Jun. 20, 1994.

In accord with the fourth major aspect of the present invention, it hasbeen discovered that one of the optical isomers of the racemic compoundsreferred to above has a biological activity which is much greater thanthat of the other isomer and that of the racemic mixture.

A further object of the present invention is therefore to provide newoptically active compounds which are useful in controlling fungaldiseases of crops.

Another further object of the invention is to provide new2-imidazolin-5-one and 2-imidazoline-5-thione derivatives which areactive at a dose which is reduced with respect to that of the racemicderivatives.

It has been found that these objects can be achieved by virtue of theproducts of the invention which are optically active 2-imidazolin-5-oneor 2-imidazoline-5-thione derivatives of general formula (I'"):##STR11## wherein: W represents an oxygen or sulfur atom or an S═Ogroup;

M represents an oxygen or sulfur atom, or an optionally halogenated CH₂radical;

p is an integer equal to 0 or 1;

* means the asymmetric carbon atom corresponding to a stereospecificconfiguration;

R₁₂ and R₂₂ are different and represent:

an alkyl or haloalkyl radical having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, monoalkylaminoalkyl,alkenyl or alkynyl radical having 2 to 6 carbon atoms;

a dialkylaminoalkyl or cycloalkyl radical having 3 to 7 carbon atoms;

an aryl radical comprising phenyl, naphthyl, thienyl, furyl, pyridyl,benzothienyl, benzofuryl, quinolyl, isoquinolyl or methylenedioxyphenyl,optionally substituted by 1 to 3 groups chosen from R₆₂ ; or

an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical,the terms aryl and alkyl having the definitions given above with respectto formula (I'");

or R₁₂ and R₂₂ can form, with the carbon to which they are bonded on thering, a carbocycle or a heterocycle having from 5 to 7 atoms, it beingpossible for these rings to be fused to a phenyl, optionally substitutedby 1 to 3 groups chosen from R₆₂ ;

R₃₂ represents:

a hydrogen or an optionally halogenated C₁ -C₂ alkyl radical, when p isequal to 0 or (M)_(p) is a CH₂ radical; or

an optionally halogenated C₁ -C₂ alkyl radical, when (M)_(p) representsan oxygen or sulfur atom;

R₄₂ represents:

the hydrogen atom;

an alkyl group having 1 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl,alkenyl or alkynyl group having 2 to 6 carbon atoms;

a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl grouphaving 3 to 6 carbon atoms;

an N,N-dialkylcarbamoylalkyl group having 4 to 8 carbon atoms;

an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolyl,isoquinolyl or methylenedioxyphenyl, optionally substituted by 1 to 3groups chosen from R₆₂ ; or

an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical,the terms aryl and alkyl having the definitions given above with respectto formula (I'");

R₅₂ represents:

H, except when R₄₂ is H;

an alkyl, haloalkyl, alkylsulfonyl or haloalkylsulfonyl radical having 1to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl, acyl, alkenyl, alkynyl, haloacyl,alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulfonyl orcyanoalkylsulfonyl radical having 2 to 6 carbon atoms;

an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl or cyanoalkoxycarbonylradical having 3 to 6 carbon atoms;

the formyl radical;

a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl oralkynylcarbonyl radical having 3 to 6 carbon atoms;

a cycloalkylcarbonyl radical having 4 to 8 carbon atoms;

a phenyl; arylalkylcarbonyl, especially phenylacetyl or phenylpropionyl;arylcarbonyl, especially benzoyl, optionally substituted by 1 to 3groups chosen from R₆₂ ; thienylcarbonyl; furylcarbonyl;pyridylcarbonyl; benzyloxycarbonyl; furfuryloxycarbonyl;tetrahydrofurfuryloxycarbonyl; thienylmethoxycarbonyl;pyridylmethoxycarbonyl; phenoxycarbonyl or (phenylthio)carbonyl, thephenyl being itself optionally substituted by 1 to 3 groups chosen fromR₆₂ ; (alkylthio)carbonyl; (haloalkylthio)carbonyl;(alkoxyalkylthio)carbonyl; (cyanoalkylthio)carbonyl;(benzylthio)carbonyl; (furfurylthio)carbonyl;(tetrahydrofurfurylthio)carbonyl; (thienylmethylthio)carbonyl;(pyridylmethylthio)carbonyl or arylsulfonyl radical;

a carbamoyl radical, optionally mono- or disubstituted by:

an alkyl or haloalkyl group having 1 to 6 carbon atoms;

a cycloalkyl, alkenyl or alkynyl group having 3 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group having 2 to 6 carbonatoms; or

a phenyl, optionally substituted by 1 to 3 R₆₂ groups;

a sulfamoyl group, optionally mono- or disubstituted by:

an alkyl or haloalkyl group having 1 to 6 carbon atoms;

a cycloalkyl, alkenyl or alkynyl group having 3 to 6 carbon atoms;

an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group having 2 to 6 carbonatoms; or

a phenyl, optionally substituted by 1 to 3 R₆₂ groups; or

an alkylthioalkylsulfonyl group having 3 to 8 carbon atoms or acycloalkylsulfonyl group having 3 to 7 carbon atoms;

or R₄₂ and R₅₂, taken together, can form, with the nitrogen atom towhich they are attached, a pyrrolidino, piperidino, morpholino orpiperazino group, optionally substituted by an alkyl having 1 to 3carbon atoms;

R₆₂ represents:

a halogen atom;

an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio oralkylsulfonyl radical having 1 to 6 carbon atoms;

a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio oralkynythio radical having 3 to 6 carbon atoms;

the nitro or cyano group;

an amino radical, optionally mono- or disubstituted by an alkyl or acylradical having 1 to 6 carbon atoms or an alkoxycarbonyl radical having 2to 6 carbon atoms; or

a phenyl, phenoxy or pyridyloxy radical, these radicals optionally beingsubstituted by 1 to 3 groups, which are identical or different, chosenfrom R₇₂ ; and

R₇₂ represents:

a halogen atom chosen from fluorine, chlorine, bromine or iodine;

a linear or branched alkyl radical having from 1 to 6 carbon atoms;

a linear or branched alkoxy or alkylthio radical having from 1 to 6carbon atoms; or

a linear or branched haloalkoxy or haloalkylthio radical having from 1to 6 carbon atoms;

a nitrile radical; or

a nitro radical.

The invention also relates to the agriculturally acceptable salifiedforms of the compounds of formula (I'").

According to a preferred variant of the fourth major aspect of theinvention, the optically active compounds according to the inventionhave the formula (I'"a): ##STR12## in which the various symbols have thesame meaning as in the formula (I'").

Finally, the compounds of the fourth major aspect of the invention willadvantageously be chosen from the compounds of formula (I'"a) in which Wrepresents an oxygen atom.

In accord with the present invention, it has been found that theconfiguration of the asymmetric carbon atom marked with an asterisk (*)in formula (I'"), i.e. in the 4-position of the ring, is very importantto the fungicidal activity of the compounds of formula (I'") and thatone of the two optical isomers, or enantiomers, has much greaterfungicidal activity than the other member of the pair. It is thereforeespecially desirable to produce the enantiomer which has the greaterfungicidal activity of the pair in optically pure form or to produceoptically active compound in a form which is greatly enriched in themore fungicidally active enantiomer, for use in fungicidal compositionsand for treating or preventing fungal disease. By "greatly enriched"form, it is meant that the optically active compound of formula (I'")contains no more than 20%, preferably no more than 5%, of the lessfungicidally active of the pair of enantiomers. In other words, when theoptically active compound of formula (I'") is in greatly enriched form,it should contain at least 80%, preferably at least 95%, of the morefungicidally active of the pair of enantiomers.

PROCESSES FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I)

The compounds of formula (Ia) can be prepared according to the processesknown per se described in the references (a) through (c) mentionedhereinabove in regard to formula (Ia) and in one of the followingreferences:

(e) Biltz, H., Chemische Berichte, 42, 1792-1802 (1909);

(f) Chattelain, M. and Cabrier, P., Bulletin de la Societe Chimique deFrance, 14, (1947), 639-642;

(g) Carrington, C. H. and Warring, W. S., Journal of the ChemicalSociety, (1950), 354-365;

(h) Lampert, K., Breuer, J. and Lemper-Streter, M., Chemische Berichte,92, 235≧239 (1959);

(i) Shalaby, A. and Daboun, H. A., Journal fur Praktische Chemie, 313(6), 1031-1038 (1971);

(j) Simig, G., Lemper, K. and Tamas, J., Tetrahedron, 29 (22 (3571-3578(1973);

(k) Schmidt, U., Heimgartner, H. and Schmidt, H., Helvetica ChemicaActa, 62 (1979), 160-170; or

(l) Muraoka, M., Journal of the Chemical Society, Perkin Transactions I,(1990), 3003-3007;

or according to one of the processes A, B, C or D described below.

The compounds of formula (Ib) can be obtained according to the processdescribed by Bohme, Martin and Strahl in Archiv der Pharmazie, 313,10-15 (1980) [reference (d) hereinabove] or according to one of theprocesses described below.

Process A: Process for the Preparation of the Compounds of Formula (I)

The preparation of the compounds of formula (I) in which A is S byS-alkylation of the 2-thiohydantoins of formula (II) below is carriedout according to the reaction scheme: ##STR13## wherein R₁, R₂, R₃, R₄,B, W and n are as defined with formula (I) hereinabove and wherein Xrepresents a chlorine, bromine or iodine atom or a sulfate group, or analkylsulfonyloxy or arylsulfonyloxy group, alkyl and aryl being asdefined above for R₁ and R₂. It is possible to use, as base, analkoxide, for example potassium tert-butoxide, an alkali metal oralkaline-earth metal hydroxide, an alkali metal carbonate or a tertiaryamine. It is possible to use, as solvent, ethers, cyclic ethers, alkylesters, acetonitrile, alcohols having 1 to 3 carbon atoms, or aromaticsolvents, for example tetrahydrofuran, at a temperature of between -5°C. and +80° C.

This process is suitable for the compounds in which W represents asulfur or oxygen atom.

The 2-thiohydantoins of formula (II) above can be obtained according toprocesses described in the literature such as, for example, in thefollowing references:

(e) Biltz, H., Chemische Berichte, 42, 1792-1801 (1909);

(n) Eberly and Dains, Journal of the American Chemical Society, 58,(1936), 2544-2547;

(o) Carrington, C. H., Journal of the Chemical Society, (1947), 681-686;

(g) Carrington, C. H. and Warring, W. S., Journal of the ChemicalSociety, (1950), 354-365;

(h) Lampert, K., Breuer, J. and Lemper-Streter, M., Chemische Berichte,92, 235-239 (1959); or

(i) Koltai, E., Nyitrai, J., Lempert, K. and Burics, L., ChemischeBerichte, 104, 290-300 (1971);

or alternatively according to one of processes E or F described belowand which form part of the invention.

Process B: Process for the Preparation of the Compounds of Formula (Ic)

The preparation of the 2-methylthio-2-imidazolin-5-ones of formula (Ic)below by cyclization of the iminodithiocarbonates of formula (V) belowis carried out according to the overall scheme: ##STR14## wherein R₁,R₂, R₄, B and n are defined as with formula (I) above.

Step (a)

The iminodithiocarbonates (III) can be prepared by carrying out thepreparation according to the conditions described in the literature foranalogous compounds, for example C. Alvarez Ibarra et al, TetrahedronLetters, 26 (2), 243-246 (1985) or E. Melendez et al, Synthesis, 1981,961, according to the scheme: ##STR15##

Step (b)

The compounds of formula (V) are obtained by condensing the compounds offormula (III) with amines or hydrazines of formula (IV). To carry outthe condensation, the acid (III) must be activated in the acid chlorideform, in the dicyclohexylisourea form using dicyclohexylcarbodiimide orin the imidazolide form using carbonyldiimidazole. Condensation iscarried out under the usual conditions for this type of reaction.

Step (c)

Cyclization of the compounds (V) is carried out by simple heating in anaromatic solvent at reflux. It is possible to use, as solvent,especially xylene, chlorobenzene or dichlorobenzene.

Process C: Derivatization of the Compounds of Formulae (Ibb) and (Idd)

Process C1: Process for the Preparation of the Compounds of Formula (Ib)by N-derivatization of the Compounds of Formula (Ibb)

The compounds of formula (Ibb), that is, the compounds of formula (Ib)in which R₅ is a hydrogen atom, can be alkylated, acylated,alkoxycarbonylated, carbamoylated or sulfamoylated according to thefollowing general scheme: ##STR16## wherein R₅ is other H, i.e. whereinR₅ represents an alkyl, alkoxycarbonyl acyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, carbamoyl or sulfamoyl group, such asdefined above with respect to formula (I); X represents a halogen, asulfate group or an optionally substituted phenoxy, or analkylsulfonyloxy or arylsulfonyloxy group, or a group R₅ O, when R₅ isacyl; and the other structural variables are defined as before withformula (I).

It is possible to use, as base, alkali metal hydrides, alkoxides or atertiary amine. The reaction can be carried out at a temperature ofbetween -30° C. and +50° C. It is possible to use as solvent, forexample, ethers, cyclic ethers, dimethylformamide, dimethyl sulfoxide oraromatic solvents.

Carbamoylation of the compounds (Ibb) can be carried out by reactingthem with isocyanates or isothiocyanates according to the scheme:##STR17##

The reaction is carried out under the same conditions as those describedabove, it being possible for the base, however, to be used in catalyticquantity.

Process C2: Process for the Preparation of the Compounds of Formula (Id)

The compounds of formula (Idd), that is, the compounds of formula (Id)in which R₂ is a hydrogen atom, can be alkylated in the 4-positionaccording to the scheme: ##STR18## wherein X represents a chlorine,bromine or iodine atom, and the other substituents are defined as beforeexcept that R₂ is other than H, in an organic solvent in the presence ofbase. It is possible to use, as base, an alkoxide, a metal hydride or anamide. The reaction can be carried out at a temperature of between -30°C. and +80° C. It is possible to use as solvent, ethers, cyclic ethers,dimethylformamide, dimethyl sulfoxide or aromatic solvents.

Process D: Process for the Preparation of S-oxidized Derivatives of the2-imidazoline-5-thiones of Formula (I)

The compounds of formula (I) in which W represents a S═O group areobtained by S-oxidizing the corresponding 2-imidazoline-5-thiones offormula (I) according to the scheme: ##STR19## wherein R₁, R₂, R₃, R₄,A, B and n are defined as before. It is possible to use peroxides,especially peracids, as the oxidizing agent. The oxidizing agent must beused in a stoichiometric quantity. Oxidation is carried out inchloroform or in methylene chloride at a temperature of between -20° C.and +20° C.

Process E: Preparation of the Dithiohydantoins of Formula (VI) Below

The dithiohydantoins of formula (VI) below can be obtained by trappingthe alpha anions of the isothiocyanates with isothiocyanates whichcannot form anions according to the scheme: ##STR20## wherein R₁, R₂ andR₄ are defined as with formula (I), provided that at least one of thegroups R₁ or R₂ must be electron-withdrawing (aryl, substituted aryl,alkoxycarbonyl, or the like). The isothiocyanate R₄ -NCS must not beable to form an anion; aryl isothiocyanates can be used in particular inthis reaction. The reaction is carried out in the presence of base. Itis possible to use, as base, potassium tert-butoxide, lithium or sodiumbis(trimethylsilyl)amide or alkali metal hydrides. It is possible to useethers or cyclic ethers as solvent. The reaction is carried out at atemperature below -60° C. The anion must be trapped as it is formed. Toachieve this, the mixture of the two isothiocyanates is run onto thebase in solution at a temperature below -60° C.

Process F: Preparation of the 2-thiohydantoins of Formula (VII) Below

The preparation of the 2-thiohydantoins (VII) from the isothiocyanatesderived from the amino acids (VIII) is carried out according to thereaction: ##STR21## wherein R₁, R₂, R₄, B and n have the same meaningsas with formula (I).

Cyclization can be carried out in two ways:

thermally: in this case, the mixture of the reactants is heated at atemperature of between 110° C. and 180° C. in an aromatic solvent, suchas toluene, xylene or the chlorobenzenes;

in basic medium: the cyclization is carried out in the presence of oneequivalent of a base, such as an alkali metal alkoxide, an alkali metalhydroxide or a tertiary amine. Under these conditions, cyclization takesplace at a temperature of between -10° C. and +80° C. It is possible touse ethers, cyclic ethers, alcohols, esters, DMF, DMSO and the like assolvent. The mixture is subsequently neutralized at room temperature.

The isothiocyanates can be prepared according to one of the processesmentioned in Sulfur Reports, 8 (5), 327-375 (1989).

Process G: Preparation of the Compounds of Formula (I) in a Single Stage

During cyclization of the 2-thiohydantoins according to process F, ifthe cyclization is carried out in basic medium, the thiohydantoin is inthe thiolate form at the end of the reaction and can be reacted directlywith an alkyl halide (chloride, bromide or iodide) or alkyl sulfate R₃ Xor with R₃ X in which X is an alkylsulfonyloxy or arylsulfonyloxy toform the corresponding compound of formula (I). Processes A and F arethus linked together according to the scheme: ##STR22## Process H:Preparation of the Compounds of Formula (Ie), that is the Compounds ofFormula (I) in which (B)n is a Sulfur Atom

These compounds can be obtained by reacting a sulfuryl chloride R₄ SClwith an imidazolinone of formula (IX) according to the scheme: ##STR23##wherein R₁, R₂, R₃ and R₄ are as defined with formula (I).

The reaction is carried out at a temperature of between -20° C. and +30°C., in the presence of one molar equivalent of a base. As base, it ispossible to use alkali metal hydrides, alkali metal alkoxides ortertiary amines. As solvent, it is possible to use polar solvents, forexample ethers, cyclic ethers, dimethylformamide, dimethyl sulfoxide oraromatic solvents. The imidazolinones of formula (IX) can be prepared byprocesses analogous to process A above.

PROCESSES FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I')

Process A

Compounds of formula (I') in which n=0, that is, compounds having theformula (I'b): ##STR24## wherein the structural variables are as definedwith formula (I') hereinabove, can be prepared according to standardprocesses described in the literature:

(1) Cyclization of an α-amino acid amide of the formula: ##STR25## witha carboxylic acid orthoester of the formula:

    R.sub.30 --C(OR').sub.3

wherein R' represents a linear or branched alkyl radical having 1 to 4carbon atoms, affords the corresponding compound of formula (I'b). Thisprocess has been described, for example, by J. Brunken and G. Bach inChem. Ber., 89, 1363-1373 (1956) and S. Ginsburg in J. Org. Chem., 27,4062-4064 (1962).

The amino acid amides of the formula (X) above can be preparedconventionally by reacting an amine of formula R₄₀ NH₂ with an aminoacid ester of formula (XI): ##STR26## The reaction can then be carriedout according to the conditions described by J. Brunken and G. Bach inChem. Ber., 89, 1363-1373 (1956).

(2) Reaction of an amine R₄₀ NH₂ with an iminoester of the formula(XII): ##STR27## affords the corresponding compound of formula (I'b).This process has been described in J. Chem. Soc., 1959, 1648 by G. Shawet al.

The iminoesters (XII) can be obtained by reaction of an amino acid ester(XI) with an imidate of the formula: ##STR28## as described in Ber. dt.Chem. Ges., 47, 2545 (1914).

(3) The compounds of formula (I'c), that is, the compounds of formula(I'b) in which R₃₀ is a hydrogen atom, can be obtained by cyclization ofan isonitrile derived from an amide of formula (XIII) in the presence ofbase, according to the scheme: ##STR29## This process has been describedby Belgian Patent Application No. 862,194 of Dec. 22, 1977.

(4) The compounds of formula (I'b) in which R₂ is other than hydrogencan be obtained by alkylation of the corresponding compounds of theformula (I'd), using a compound of the formula R₂ X as the alkylatingagent, in basic medium according to the method described in theabove-mentioned Belgian patent application, according to the scheme:##STR30## wherein R₂ is other than hydrogen.

(5) Reaction of an amine of the formula R₄₀ NH₂ with an azalactone ofthe formula (XIV): ##STR31## affords the corresponding compound offormula (I'b). This reaction can be carried out by acid catalysis(acetic acid, for example) or by basic catalysis. An example of thelatter case can be found in the article by Ito et al, Yakugaku Zasshi,1975, 95(1), 28-32.

PROCESS B:

The compounds of formula (I'a) can be obtained by analogy with one ofthe above-mentioned processes by reacting a hydrazine derivative of theformula R₄₀ NR₅ NH₂ in place of the amine derivative of the formula R₄₀NH₂. They can also be prepared according to a process which forms partof the invention, by hot cyclization of a hydrazide of the formula (XV):##STR32## The reaction is catalyzed by acids. Inorganic acids,alkylsulfonic acids, arylsulfonic acids, acidic resins or carboxylicacids can be used as the acid. The reaction can be carried out inaromatic solvents, halogenated hydrocarbons, ethers, cyclic ethers,esters or alcohols. It is carried out at a temperature between 50° C.and 150° C. The reaction is generally carried out at the refluxtemperature of the solvent, the water being distilled off as it isformed.

The hydrazides of formula (XV) can be prepared according to one of theprocesses described in the literature, for example as enumerated below:

(1) Reaction of certain hydrazines of the formula R₄₀ NR₅ NH₂ withcertain methyl, ethyl, propyl or butyl amino acid esters of the formula:##STR33## as described by German Patent Application 1,089,390 of Sep.22, 1960 (Chem., Ab., 1962, 56, 4860-4862), provides the correspondinghydrazides.

(2) Condensation of an N-acylated amino acid with a hydrazine in thepresence of papain extracts in buffered aqueous solution according tothe article by Niemann and Nichols in J. Biol. Chem., 143, 1942,191-201, affords the corresponding hydrazide.

(3) Reaction of a hydrazine R₄₀ NR₅ NH₂ with an azalactone of formula(XIV) hereinabove according to the reference by J. P. Branquet et al.,Bull. Soc. Chim. de France, 1965, (10), 2942-2954, affords thecorresponding hydrazides.

The azalactones of formula (XIV) are themselves described in theabove-mentioned article.

(4) A preferred general access route analogous to process B(2) aboveconsists in activating the acid in the imidazolide form (Reaction a) orthe mixed anhydride form (Reaction b) in order to condense it with ahydrazine, as depicted below: ##STR34## The condensation is carried outunder the usual conditions for this type of reaction, as is illustratedin Examples 12 and 13 hereinbelow.

PROCESS C:

Another preferred route for preparing the compounds of formula (I'a)consists in reacting a hydrazine of the formula R₄₀ NR₅ NH₂ with anazalactone of the formula (XIV) hereinabove under certain conditions:

(1) By heating the reactants in an inert solvent in the presence of anacid in order to catalyze the reaction. Halogenated hydrocarbons,esters, aromatic solvents or alcohols can be used as the solvent.Inorganic acids, alkylsulfonic acids, arylsulfonic acids, acidic resinsor carboxylic acids can be used to catalyze the reaction. The reactionis carried out at a temperature from 50° C. to 150° C.

This process is illustrated in Example 15 hereinbelow.

(2) By heating the mixture of the reactants in acetic acid at reflux inthe presence of sodium acetate in order to catalyze the reaction.

These conditions are illustrated in Example 16 hereinbelow.

PROCESS D:

The compounds of formula (I'a) in which R₅ is other than a hydrogen atomare also possible starting from compounds of the formula (I'aa) below,which can be alkylated, acylated, alkoxycarbonylated, carbamoylated orsulfamoylated by R₅ X in the presence of base and solvent: ##STR35##wherein R₅ here represents an alkyl, alkoxycarbonyl, acyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, carbamoyl or sulfamoyl group, as definedabove, and X represents a halogen, a sulfate or optionally substitutedphenoxy group, or an alkylsulfonyloxy or arylsulfonyloxy group, or agroup R₅ O, when R₅ is acyl.

Alkali metal hydrides, alkoxides or a tertiary amine can be used asbase. The reaction can be carried out at a temperature between -30° C.and +50° C. Ethers, cyclic ethers, dimethylformamide, dimethyl sulfoxideor aromatic solvents, for example, can be used as solvent.

The carbamoylation or the thiocarbamoylation of the compounds of theformula (I'aa) can be carried out by reaction with isocyanates orisothiocyanates according to the scheme: ##STR36## The reaction iscarried out under the same conditions as those described above, it beingpossible, however, for the base to be used in a catalytic amount.

PROCESS E:

The compounds of formula (I'ab) below, which are compounds of formula(I'a) in which the group R₃₀ is a hydrogen atom, can be obtained byreaction of dimethylformamide dimethyl acetal (DMFDMA) with anaminohydrazide of formula (XVI) according to the scheme: ##STR37## Thereaction is carried out at a temperature between 10° C. and 100° C. inDMFDMA used in excess.

The intermediate aminohydrazides of formula (XVI) can be obtainedaccording to a new process by reacting the hydrochloride of the acidchloride of the corresponding α-amino acid in the presence of a baseaccording to the scheme: ##STR38## The reaction is carried out at atemperature between -20° C. and 40° C. in cyclic or noncyclic ethers.Nitrogenous organic bases such as triethylamine or pyridine can beoptionally used as the base. The intermediate acid chlorides can beobtained by the method described by S. Levine in J. Am. Chem., Soc.,1953, Volume 76, 1392, They are then obtained by reacting phosphoruspentachloride with the α-amino acid according to the scheme below:##STR39##

PROCESSES FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I")

The compounds of formula (I") are obtained by reacting2-alkylthio-2-imidazolin-5-ones of formula (XVII) with an alcohol R₃₁ OHin the presence of strong base, according to the scheme: ##STR40##wherein R₁₁, R₂₁, R₃₁ and R₄₁ have the same meaning as in formula (I")hereinabove and R'₃₁ represents an alkyl group having from 1 to 3 carbonatoms.

As the strong base, an alkali metal alkoxide R₃₁ O⁻ M⁺, an alkali metalhydroxide or a strong organic base can be used. The reaction ispreferably carried out in the alcohol R₃₁ OH as solvent, using thecorresponding sodium alkoxide R₃₁ O⁻ Na⁺ as base. The reaction iscarried out at a temperature of between about 20° C. and 80° C. The2-alkylthio-2-imidazolin-5-ones of formula (XVII) are obtained accordingto one of the processes described hereinabove for the preparation ofcompounds of formula (I), in particular, for the preparation ofcompounds of formula (Ib) hereinabove. The acylation of the compounds offormula (I") in which R⁵¹ is a hydrogen atom, takes place according toclassical methods.

Agriculturally acceptable salts of the compounds of formula (I") may beprepared by known methods.

PROCESSES FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I"')

The method of preparation of the compounds of formula (I"') is describedin the following paragraphs, according to two process variants A and B.The symbols represented in formula (I"') and its intermediates whichappear in this description of the method of preparation retain the samemeaning as in the general definition of the compounds of formula (I"')hereinabove, unless another definition is expressly attributed to them.

Variant A:

First Stage:

A first stage of this variant consists of the preparation of the opticalisomers of formula (I"') from α-amino acids which are optionally pure orgreatly enriched in one enantiomer. Optically active compound greatlyenriched in a specific enantiomer is understood to mean a compoundcontaining at least 80%, preferably 95%, of this enantiomer.

The optical isomers of formula (I"') are prepared according to threeseries of processes, depending on the meaning of the (M)_(p) --R₃₂group.

Process (1): Preparation of the compounds of formula (I"') in which p=1and M=S and W=O:

The compounds of formula (I"') in which p=1 and M=S and W=O are preparedby reaction of the compound of formula (XVIII): ##STR41## wherein Wrepresents an oxygen atom, with the compound of formula R₃₂ X, in whichX represents the chlorine, bromine or iodine atom or the sulfate groupor an alkylsulfonyloxy or arylsulfonyloxy group, alkyl and aryl being asdefined above for R₁₂ and R₂₂. The reaction is carried out in a solventand in the presence of a base. It is possible to use, as base, analkoxide, for example potassium tert-butoxide, an alkali metal oralkaline-earth metal hydroxide, an alkali metal carbonate or a tertiaryamine. It is possible to use, as solvent, ethers, cyclic ethers, alkylesters, acetonitrile, alcohols containing 1 to 3 carbon atoms oraromatic solvents, for example tetrahydrofuran, at a temperature between-5° C. and +80° C.

A variant of the method described above consists in applying theso-called "one-pot" process depicted below, which is describedhereinabove for the preparation of compounds of formula (I). This methodconsists in starting directly from the isothiocyanate of formula (XIX)which is treated with a compound of formula (XX) in a solvent and in thepresence of a base as described above. The intermediate of formula(XVIIIa) in the salt form is not isolated but is treated directly withthe compound of formula R₃₂ X in which X has the same meaning as in thepreceding paragraph. ##STR42## R is typically C₁ -C₆ alkyl in formula(XIX) above.

The compound of formula (XVIII) in which W represents an oxygen atom canbe prepared by a cyclization reaction between an isothiocyanate offormula (XIX): ##STR43## wherein R represents C₁ -C₄ alkyl, and acompound of formula (XX): ##STR44##

The cyclization reaction can be carried out in two ways:

(a) thermally in this case, the mixture of the reactants is heated at atemperature between 110° C. and 180° C. in an aromatic solvent such astoluene, xylene or chlorobenzenes;

(b) in the basic medium: the cyclization reaction is carried out in thepresence of one equivalent of base such as an alkali metal alkoxide, analkali metal hydroxide or a tertiary amine. Under these conditions,cyclization takes place at a temperature between -10° C. and +80° C. Itis possible to use, as solvent, especially ethers, cyclic ethers,alcohols, esters, DMF or DMSO.

The isothiocyanates of formula (XIX) can be prepared according to one ofthe processes mentioned in Sulfur Reports, Volume 8 (5), 327-375 (1989),from the α-amino acid of formula (XXI) via the amino ester of formula(XXII): ##STR45## in a way well known to those skilled in the art.

The amino esters of structure (XXII) can be obtained in a known way by:

(a) diastereoselective amination of a prochiral compound followed bydeprotection of the chiral moiety as described by R. S. Atkinson et al,Tetrahedron, 1992, 48, 7713-30;

(b) resolution of the corresponding racemate with a chiral compound asdescribed by Y. Sugi and S. Mitsui, Bull, Chem. Soc. Japan, 1969, 42,2984-89; or

(c) esterification of a chiral amino acid as described by D. J. Cram etal., J. Am. Chem. Soc., 1961, 83, 2183-89.

Process (2): Preparation of the optical isomers of formula (I"') inwhich p=1 and M=O and W=O:

The compounds of formula (I"') in which p=1 and M=O and M=O are preparedby reacting the corresponding compound of formula (I"') in which p=1 andM=S [according to a process described hereinabove for the preparation ofcompounds of formula (I)] with an alcohol of the formula R₃₂ OH, in asolvent, in the presence of a strong base and at a temperature between50° C. and 80° C. It is possible to use, as the strong base, an alkalimetal alkoxide R₃₂ O⁻ Met⁺, in which Met⁺ represents an alkali metal oralkaline-earth metal, an alkali metal hydroxide or a strong organicbase. The reaction is preferably carried out by selecting the alcoholR₃₂ OH as solvent and by using the corresponding sodium alkoxide R₃₂ O⁻Na⁺ as base.

Process (3): Preparation of the optical isomers of formula (I"') inwhich p=O:

The compounds of formula (I"') in which p=0 and R₃₂ is a hydrogen atomare obtained from the corresponding compound of formula (XXIII):##STR46## by reacting the latter with dimethyformamide dimethyl acetal(DMFDMA). The reaction is carried out at a temperature between 10° C.and 100° C., in excess DMFDMA.

The compound of formula (XXIII) is prepared from a compound of formula(XXIV): ##STR47## by reaction of the latter with the compound of formula(XX) above, at a temperature between -20° C. and 40° C., in a solventconsisting of a cyclic or non-cyclic ether, optionally in the presenceof a base. The base is chosen from nitrogenous organic bases such astriethylamine or pyridine.

The compounds of formula (XXIV) can be obtained from the α-amino acid offormula (XXI) by observing the method described by S. Levine in J. Am.Chem. Soc., 1953, Volume 76, 1392.

The optically active compounds of formula (I"') in which R₃₂ is anoptionally halogenated C₁ -C₂ alkyl radical and in which p=0 or p=1 andM=CH₂ are obtained from the compound of formula (XXV): ##STR48## inwhich R₃₂ represents a C₁ -C₃ alkyl radical, by reaction of the latterwith the compound of formula (XX) above, under conditions deduced, byanalogy, from the method set out in the article by J. P. Branquet, etal. in Bull. Soc. Chim. de France, 1965, (10), 2942-2954.

The same article gives a procedure at the end of which the compound offormula (XXV) can be prepared from the α-amino acid of formula (XXI).

Second Stage:

The method of access to the optically pure or greatly enriched α-aminoacids of formula (XXI) used in the above stage is specified in thissecond stage of Variant A.

These α-amino acids can be obtained according to one of the followingmethods:

(1) by diastereoselective synthesis and then suppression of the chiralmoiety, as described by M. Chaari, A., Jenhi, J. P. Lavergne and P.Viallefont in Tetrahedron, 1991, 4, 4619-4630,

(2) by enzymatic resolution of the racemic amide, for which method thefollowing references may usefully be consulted:

R. M. Kellog, E. M. Meijer et al., J. Org. Chem., 1988, 53, 1826-1828;and

D. Rossi and a. Calcagni, Experimentia, 1985, 41, 35-37;

(3) by hydrolysis of a chiral amino acid precursor such as, for example:

(a) a formyl amino acid of structure (XXVI) below, as described byMacKenzie and Clough, J. Chem. Soc., 1912, 390-397, or by D. J. Cram etal. J. Am. Chem. Soc., 1961, 83, 2183-89; or

(b) a hydantoin of structure (XXVII) as described in published BritishPatent Application No. 1,201,168: ##STR49##

The compounds of formulae (XXVI) and (XXVII) can be obtained byresolution of the corresponding racemic modification with a chiralcompound as described by MacKenzie and Clough, J. Chem. Soc., 1912,390-397, or by D. J. Cram et al, J. Am. Chem. Soc., 1961, 83, 2183-89,for the compound (XXVI); or as described in published InternationalPatent Application No. 92/08702 for the compound (XXVII).

Variant B:

According to a second variant of the process for the preparation of theoptical isomers of formula (I"'), the latter are obtained from thecorresponding racemic compounds by high performance liquidchromatography on a chiral stationary phase. A chiral stationary phaseof Pirkle type with D-phenylglycine grafts is preferred.

The racemic compounds corresponding to the formula (I"') are preparedaccording to the methods described hereinabove for the preparation ofthe compounds of formulas (I), (I'), and (I"), which are the methodsdescribed and exemplified in parent U.S. Ser. No. 07/993,700, filed Dec.21, 1992, parent U.S. Ser. No. 08/156,647, filed Nov. 24, 1993, andparent International Application No. PCT/FR93/00647, filed Jun. 29,1993.

Another subject of the present invention is new optically activecompounds useful especially as intermediates in the preparation of thecompounds of formula (I"'). These intermediates have the formulae(XVIII), (XIX), (XXI), (XXIII), (XXIV) and (XXII): ##STR50## whereinR₁₂, R₂₂, R₄₂ and R₅₂ have the same meanings as in the general formula(I"') of the invention;

and the formula (XXV): ##STR51## wherein R₁₂ and R₂₂ have the samemeaning as above and R₃₂ represents an optionally halogenated C₁ -C₃alkyl radical;

and the formula (XXVIIb): ##STR52## wherein R₂₂ has the same meaning asabove and R₆₂ represents a phenyl, phenoxy or pyridyloxy radical, theseradicals optionally being substituted by 1 to 3 groups, which areidentical or different, chosen from R₇₂ as defined above.

The EXAMPLES below are given by way of illustration only of thecompounds according to the invention, of the processes for theirpreparation and of their antifungal properties.

The structures of all the products were established by at least one ofthe following spectral techniques: proton NMR spectrometry, carbon-13NMR spectrometry, infrared spectrometry and mass spectrometry.

EXAMPLES OF THE PREPARATION OF COMPOUNDS OF FORMULA (I) ANDINTERMEDIATES THERETO

In the tables below, the methyl and phenyl radicals are representedrespectively by Me and Ph, and Cst means a physical constant, that is tosay, either a melting point (M.p.) or the refractive index (n_(D) ²⁰).

EXAMPLE 1

Preparation of Compound 34 according to Process A.

0.9 g (3 mmol) of 3-benzyl-5-methyl-5-phenyl-2-thiohydantoin isdissolved in 30 ml of anhydrous tetrahydrofuran. The mixture is cooledto 0° C. and then 0.34 g (3 mmol) of potassium tert-butoxide is added.The mixture is left to react for 10 minutes at 0° C. and then 0.46 g(3.3 mmol) of methyl iodide is run in dropwise at this temperature:potassium iodide is observed to precipitate. The temperature of themixture is allowed to return to room temperature. The mixture is dilutedwith 100 ml of ethyl acetate. The solution is washed 2 times with 100 mlof water on each occasion. The solution is dried over sodium sulfate andis then treated with active charcoal. The solution is concentrated underreduced pressure: 0.6 g of1-benzyl-4-methyl-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 34)is recovered in the form of a pale-yellow solid melting at 68° C.

The compounds described below were prepared in the same way:

    ______________________________________                                          #STR53##                                                                    No.  R.sub.2                                                                             R.sub.3   R.sub.4   R.sub.5                                                                            W   Cst                                   ______________________________________                                           1 Me Me Ph H S M.p. = 127° C.                                          3 Me 2-oxopropyl Ph H S M.p. = 130° C.                                 9 Me Me Ph H O M.p. = 149° C.                                         10 Me Me meta-tolyl H O M.p. = 124° C.                                 11 Me Me para-tolyl H O M.p. = 150° C.                                 12 Me Et Ph H O M.p. = 118° C.                                         13 Me Me 4-fluoroPh H O M.p. = 144° C.                                 14 Me allyl Ph H O M.p. = 92° C.                                       15 Me Me ortho-tolyl H O M.p. = 92° C.                                 16 Me Me 3-chloroPh H O M.p. = 120° C.                                 17 Me isopropyl Ph H O M.p. = 95° C.                                   18 Me Me 4-chloroPh H O M.p. = 149° C.                                 19 Me Me tert-butyl H O M.p. = 73° C.                                  20 Me Me 2-chloroPh H O M.p. = 134° C.                                 22 Me Me Ph Me O M.p. = 124° C.                                        23 Me Me Ph acetyl O M.p. = 132° C.                                    24 Me Me 4-methoxyPh H O M.p. = 138° C.                                25 Me n-propyl Ph H O M.p. = 90° C.                                    40 Me Me 2-methoxyPh H O M.p. = 110° C.                                41 Me Me acetyl H O M.p. = 55° C.                                      43 Me Me 4-NO.sub.2 --Ph H O M.p. = 133° C.                            44 Me Me 2-pyridyl H S M.p. = 114° C.                                  45 Me Me 2-pyridyl H O M.p. = 147° C.                                  46 Me Me 3-pyridyl H O M.p. = 140° C.                                  47 Me Me 3-pyridyl H S M.p. = 176° C.                                  54 Me Me 2,6-Me.sub.2 Ph H S M.p. = 146° C.                            73 Me Me 2-thiazolyl Me O M.p. = 116° C.                               75 Me CHF.sub.2 Ph H O M.p. = 80° C.                                   80 Me Me 3-pyridyl-CH═ -- O M.p. = 92° C.                          81 Me Me 2-pyridyl-CH═ -- O M.p. = 106° C.                         82 Me Me 4-Me--SO.sub.2 --Ph H O M.p. = 130° C.                      ______________________________________                                          #STR54##                                                                      No.    R.sub.2                                                                              R.sub.3                                                                            R.sub.4                                                                              n   R.sub.5                                                                             W    Cst                                ______________________________________                                          26 Me Me Ph 0 -- S M.p. = 123° C.                                      27 Ph Me Ph 0 -- S M.p. = 120° C.                                      28 Me Me Me 0 -- S M.p. = 85° C.                                       29 Ph Me Me 0 -- S M.p. = 144° C.                                      30 Me Me Ph 0 -- O M.p. = 70° C.                                       31 Me Me Me 0 -- O M.p. = 58° C.                                       32 Ph Me Me 0 -- O M.p. = 170° C.                                      33 H Me Ph 0 -- O M.p. = 250° C.                                       34 Me Me Ph 1 H O M.p. = 68° C.                                        35 Me Me 2-thienyl 1 H O M.p. = 76° C.                                 36 Me Me Me 1 Me O n.sub.D.sup.20 = 1.553                                     37 Me Me 2-furyl 1 H O "honey-like                                                   consistency"                                                           38 Me Me 3-pyridyl 0 -- O "honey-like                                                consistency"                                                           50 Ph Me Me 0 H S M.p. = 144° C.                                       52 Me Me Ph 1 CO.sub.2 Me O "honey-like                                              consistency"                                                           57 Me Me 2-MePh 0 -- O "honey-like                                                   consistency"                                                         ______________________________________                                    

The following were also prepared:

4-(3-pyridyl-4-methyl-1-(N-phenylamino)-2-methylthio-2-imidazolin-5-one(Compound 51: M.p. 156° C.);

4-phenyl-4-methyl-1-(benzyloxy-2-methylthio-2-imidazolin-5-one (Compound56: honey-like consistency).

EXAMPLE 2

Preparation of Compound 7 according to Process B.

(a) N-[bis(methylthio)methylene]-2-phenylglycine [compound (III) inwhich R₁ =phenyl and R₂ =H]:

100 g (0.66 mol) of phenylglycine are dissolved at +5° C. in 335 g of22% aqueous potassium hydroxide (1.3 mol). 55.3 g of carbon disulfideare added while stirring the mixture vigorously: a precipitate appearsand the mixture turns orange in color. The mixture is left to react for3 hours at room temperature and then 103 g (0.73 mol) of methyl iodideare run in while keeping the temperature of the mixture below 30° C. Themixture is left to react for 0.5 hour and then 74 g (0.66 mol) of a 50%potassium hydroxide solution are added. The mixture is left to react for0.5 hour and then 103 g of methyl iodide are again run in and left toreact for 1 hour. The mixture is diluted with 300 ml of water. Themixture is acidified to pH=4 with 1 N hydrochloric acid. The product isextracted with 500 ml of ethyl acetate. The solution is dried overmagnesium sulfate and then concentrated under reduced pressure. 49.5 gof N-[bis(methylthio)methylene]-2-phenylglycine (yield=31%) arerecovered in the form of a yellow solid melting at 112° C.

(b) 2'-(metachlorophenyl)[N-(bis(methylthio)methylene)-2-phenylglycyl]hydrazide (compound V withR₁ =phenyl, R₂ =H, R₄ =metachlorophenyl, n=1, B=NH):

3.38 g (16.4 mmol) of dicyclohexylcarbodiimide are added to a solutionof 2.95 g (16.4 mmol) of N-[bis(methylthio)methylene]-2-phenylglycine inmethylene chloride (40 ml), and the mixture is then left to react for0.5 hour at room temperature. 2.34 g (16.4 mmol) ofmetachlorophenylhydrazine are added. The mixture is heated for 0.5 hourat 30° C. The insoluble material is filtered off. The filtrate is washedwith 2 times 30 ml of water on each occasion. The solution isconcentrated: a honey-like product is obtained which is purified bychromatography on a silica column. After purification, 2.5 g of2'-(metachlorophenyl)[N-(bis(methylthio)methylene)-2-phenylglycyl]hydrazide are recovered inthe form of a pinkish powder melting at 146° C.

(c) 1-Metachlorophenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one(compound 7):

1.92 g (5 mmol) of 2'-(metachlorophenyl)[N-(bis(methylthio)methylene)-2-phenylglycyl]hydrazide is dissolved in30 ml of xylene. The reaction mixture is heated for 4 hours at reflux.The mixture is concentrated under reduced pressure. The resultinghoney-like product is triturated with 10 ml of ether: the productcrystallizes. The precipitate is filtered and the product is dried in adesiccator under vacuum. Compound 7 is thus obtained, with a yield of56%, in the form of a yellow powder melting at 196° C.

By carrying out the preparation in a similar way, the compounds whichappear in the following table were prepared:

    ______________________________________                                          #STR55##                                                                    No.  R.sub.2                                                                              R.sub.3                                                                              R.sub.4   R.sub.5                                                                            W    Cst                                    ______________________________________                                        4    H      Me     2-chloroPh                                                                              H    O    M.p. = 130° C.                    5 H Me Ph H O M.p. = 190° C.                                           6 H Me 4-chloroPh H O M.p. = 162° C.                                   7 H Me 3-chloroPh H O M.p. = 196° C.                                   8 H Me mera-tolyl H O M.p. = 182° C.                                   59 H Me 2,4-(CH.sub.3).sub.2 Ph H O M.p. = 64° C.                      61 H Me 2,5-(CH.sub.3).sub.2 Ph H O M.p. = 162° C.                     63 H Me 2-EtPh H O M.p. = 126° C.                                      69 H Me 2,5-(Cl).sub.2 Ph H O M.p. = 144° C.                           71 H Me 3,5-(Cl).sub.2 Ph H O M.p. = 146° C.                         ______________________________________                                    

4-Phenyl-1-(N-phenylamino)-2-methylthio-2-imidazolin-5-one (Compound120) was also prepared.

EXAMPLE 3

Preparation of4-methyl-1-(N-methyl-N-phenylamino)-2-methylthio-4-phenyl-2-imidazolin-5-one(Compound 22) by alkylation (methylation) according to Process C1:

0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one(Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml),cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at0° C. 0.5 g (3.5 mmol) of methyl iodide is then added and then themixture is left to react for 0.5 hour at room temperature. The reactionmixture is poured into 100 ml of water and the product is extracted with100 ml of diethyl ether. The ethereal solution is dried over magnesiumsulfate and then concentrated. The product crystallizes when trituratedin 10 ml of diisopropyl ether. It is filtered and then dried undervacuum. 0.73 g (yield: 70%) of Compound 22 is thus obtained in the formof a pale-yellow powder melting at 124° C.

EXAMPLE 4

Preparation of4-methyl-1-(N-acetyl-N-phenylamino)-2-methylthio-4-phenyl-2-imidazolin-5-one(Compound 23) by acylation (actylation) according to Process C1:

0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one(Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml),cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at0° C. 0.25 g (3.5 mmol) of acetyl chloride is then added and the mixtureis left to react for 0.5 hour at room temperature. The reaction mixtureis poured into 100 ml of water and the product is extracted with 100 mlof diethyl ether. The ethereal solution is washed with water toneutrality. The solution is dried over magnesium sulfate and thenconcentrated. A honey-like product is obtained which is purified bychromatography on a silica column. The purified product crystallizesfrom diisopropyl ether. 0.25 g of Compound 23 is obtained in the form ofa white powder melting at 132° C.

By carrying out the preparation in the same way, Compounds 39 and 42were obtained.

    ______________________________________                                          #STR56##                                                                    No.     R.sub.2                                                                              R.sub.3                                                                              R.sub.4                                                                            R.sub.5 W    Cst                                   ______________________________________                                        23      Me     Me     Ph   acetyl  O    M.p. = 132° C.                   39 Me Me Ph formyl O "honey-like                                                    consistency"                                                            42 Me Me Ph tBuOCO O "honey-like                                                    consistency"                                                          ______________________________________                                    

EXAMPLE 5

Preparation of4-ethyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one (Compound48) according to Process C2:

0.55 g of potassium tert-butoxide is added to a solution of 1.5 g (5.05mmol) of 2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one(Compound 5) in 50 ml of anhydrous tetrahydrofuran. The mixture is leftto react for 30 minutes at room temperature and then 0.8 g (5.05 mmol)of ethyl iodide is added. The mixture is left to react for 1 hour atroom temperature. The mixture is diluted with 150 ml of ethyl acetate.The solution is washed with water and then concentrated under reducedpressure. The product is purified by chromatography on a silica column(Merck 60H silica; eluent: 25% ethyl acetate/75% heptane). 0.65 g ofCompound 48 is obtained in the form of a beige powder melting at 147° C.

By carrying out the preparation in the same way, Compound 49 wasobtained. The other compounds listed below can also be obtained in thismanner.

    ______________________________________                                        No.   R.sub.2 R.sub.3                                                                              R.sub.4  R.sub.5                                                                            W    Cst                                   ______________________________________                                        48    Et      Me     Ph       H    O    M.p. = 147° C.                   49 iso-Pr Me Ph H O M.p. = 135° C.                                     60 Me Me 2,4(Me).sub.2 Ph H O "honey-like                                           consistency"                                                            62 Me Me 2,5-(Me).sub.2 Ph H O M.p. = 160° C.                          64 Me Me 2-EtPh H O "honey-like                                                     consistency"                                                            65 Me Me 2,4-(Cl).sub.2 Ph H O                                                66 Me Me 1-naphthyl H O M.p. = 174° C.                                 70 Me Me 2,5-(Cl).sub.2 Ph H O M.p. = 180° C.                          72 Me Me 3,5-(Cl).sub.2 Ph H O M.p. = 200° C.                          74 CHF.sub.2 Me Ph H O M.p. = 124° C.                                  79 Me Me 2-CF.sub.3 --Ph H O M.p. = 91° C.                           ______________________________________                                    

4-Methyl-2-methylthio-4-(4-fluorophenyl)-1-phenylamino-2-imidazolin-5-one(Compound 68) was also prepared.

EXAMPLE 6

Preparation of Compound 2 according to Process D:

1.7 g (5.2 mmol) of4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazoline-5-thione(compound 1) is dissolved in 20 ml of chloroform. The solution is cooledto -10° C. and then a solution of 1.35 g (5.5 mmol) ofmetachloroperbenzoic acid and 30 ml of chloroform is added over 10minutes. On completion of addition, the temperature is allowed to returnto room temperature. The mixture is washed with a saturated aqueoussodium bicarbonate solution and then with distilled water. The organicphase is treated with active charcoal and then concentrated. Theresulting honey-like product is taken up in 20 ml of ether: the productdissolves and then a beige solid precipitates. The precipitate isfiltered. The product is dried under reduced pressure. 0.4 g (yield:25%) of Compound 2 is thus obtained in the form of a beige powdermelting at 150° C.

    ______________________________________                                        No.     R.sub.2                                                                             R.sub.3 R.sub.4                                                                           R.sub.5                                                                             W    Cst                                      ______________________________________                                        2       Me    Me      Ph  H     S═O                                                                            M.p. = 150° C.                    ______________________________________                                    

EXAMPLE 7

Preparation of 3,5-diphenyl-5-methyldithiohydantoin according to ProcessE:

15.1 g (122 mmol) of potassium tert-butoxide are dissolved in 200 ml oftetrahydrofuran in a 500 ml, three-necked, round-bottomed flask under adry argon atmosphere. The solution is cooled to -70° C. A solutioncontaining 20 g (122 mmol) of alpha-methylbenzyl isothiocyanate, 16.55 g(122 mmol) of phenyl isothiocyanate and 50 ml of tetrahydrofuran is runin dropwise while keeping the temperature of the mixture below -60° C.On completion of addition, the mixture is held for 0.5 hour at -70° C.and then is left to return to room temperature. The mixture is pouredinto 500 ml of water. The mixture is acidified to pH=1 by addition of Nhydrochloric acid. The product is extracted with ethyl acetate (2extractions, each with 150 ml of solvent). The solution is dried overmagnesium sulfate. The solution is concentrated under reduced pressure.The product is crystallized from 50 ml of ether. The precipitate isfiltered. 21 g (yield: 58%) of 3,5-diphenyl-5-methyldithiohydantoin arethus obtained as a yellow powder melting at 157° C.

EXAMPLE 8

Preparation of 3,5-diphenyl-5-methyl-2-thiohydantoin according toProcess F:

4.7 g (20 mmol) of ethyl 2-isothiocyanato-2-phenylpropionate aredissolved in 40 ml of xylene. 2.16 g (20 mmol) of phenylhydrazine areadded and the mixture is heated for 4 hours at reflux. The mixture iscooled to room temperature and a beige solid precipitates. Theprecipitate is filtered, washed with 5 ml of diisopropyl ether and thendried under vacuum. 4.6 g (yield=77%) of3,5-diphenyl-5-methyl-2-thiohydantoin are thus obtained in the form of abeige powder melting at 164° C.

EXAMPLE 9

Preparation of 5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoinaccording to Process F:

2 g (9 mmol) of methyl 2isothiocyanato-2-phenylpropionate are dissolvedin 30 ml of tetrahydrofuran. A solution containing 0.99 g of 2-hydrazinopyridine and 10 ml of tetrahydrofuran is added: thetemperature of the mixture rises from 20 to 30° C. and a solidprecipitates. The mixture is allowed to react for 0.5 hour at 30° C. andthen is cooled to 5° c. A solution containing 1 g of potassiumtert-butoxide and 10 ml of tetrahydrofuran is then added: the mixturebecomes violet in color. The mixture is left to return to roomtemperature and is left to react for 2 hours. The mixture is poured into150 ml of water. The mixture is neutralized with acetic acid. Theproduct is extracted with 150 ml of ethyl acetate. The solution iswashed with water, dried over magnesium sulfate and then treated withactive charcoal. The solution is concentrated and the product iscrystallized from 20 ml of diethyl ether. The above-mentioned product isfiltered and is dried under vacuum. 1.6 g (yield: 60%) of5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoin is obtained as apale-yellow solid melting at 80° C.

The compounds of formula (VII) collated in the following table, whichare intermediates of the compounds of formula (I) and are numbered fromnumber 1001, were prepared according to this process:

    ______________________________________                                                                      (VII)                                                                           #STR57##                                      wherein R.sub.1 = methyl and R.sub.2 = phenyl:                                  No.       n      B     R.sub.4 Yield   M.p.                                 ______________________________________                                        1001    1      NH      Ph      66%     164° C.                           1002 1 NH meta-tolyl 62% 174° C.                                       1003 1 CH.sub.2 Ph 46% 125° C.                                         1004 1 NH para-tolyl 13% 162° C.                                       1005 1 CH.sub.2 2-thienyl   49.5% 134° C.                              1006 1 NH 4-fluoroPh 30% 162° C.                                       1007 1 NH ortho-tolyl 38% 162° C.                                      1008 0 -- isopropyl   60.5% 146° C.                                    1009 1 NH 3-chloroPh 32% 78° C.                                        1010 1 NH tert-butyl 18% 120° C.                                       1011 1 NH 4-chloroPh 24% 196° C.                                       1012 1 NH 2-chloroPh 69% 172° C.                                       1013 0 -- piperidino 32% 206° C.                                       1014 1 NH 4-methoxyPh 27% 146° C.                                      1015 1 NH 2-methoxyPh 29% 214° C.                                      1016 1 CH.sub.2 2-furyl 39% 105° C.                                    1017 1 NH acetyl 42% 200° C.                                           1018 1 NH 4-NO.sub.2 --Ph 41% 234° C.                                  1019 1 NH 2-pyridyl 60% 80° C.                                         1020 1 NH 3-pyridyl 17%                                                     ______________________________________                                    

EXAMPLE 10

Preparation of Compound 9 according to Process G:

11.1 g (50 mmol) of methyl 2-isothiocyanato-2-phenylpropionate aredissolved in 150 ml of anhydrous tetrahydrofuran. A solution containing5.4 g (50 mmol) of phenylhydrazine and 50 ml of anhydroustetrahydrofuran is added progressively over 10 minutes: the temperatureof the mixture rises to 35° C. On completion of addition, the mixture isleft to react for 0.5 hour at 30° C. and the mixture is then cooled to-5° C. A solution containing 5.6 g (50 mmol) of potassium tert-butoxideand 50 ml of anhydrous tetrahydrofuran is added at this temperature: themixture turns violet in color and then a precipitate forms. The mixtureis left to react for 0.5 hour at 0° C. and then 8.5 g (60 mmol) ofmethyl iodide are added. The mixture is left to react for 1 hour at roomtemperature. The mixture is diluted with 200 ml of ethyl acetate. Themixture is washed 2 times with 150 ml of water on each occasion. Thesolution is dried over magnesium sulfate and then treated with activecharcoal. The solution is concentrated: a purplish-brown honey-likeproduct is obtained which is crystallized from 50 ml of ether. Theprecipitate is washed and then dried under vacuum. A second crop ofproduct is recovered after concentrating the mother liquors and takingup the residual honey-like product in 50 ml of diisopropyl ether. 12 g(yield=77%) of4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one(Compound 9) are thus obtained in the form of a beige powder melting at149° C.

By carrying out the preparations as above, the following compounds wereobtained:

    ______________________________________                                          #STR58##                                                                    No.  R'.sub.1  R.sub.2                                                                             R.sub.3                                                                            B     R.sub.4  M.p.                                 ______________________________________                                        58   --        Me    Me   NH    2,3-(Me).sub.2 Ph                                                                      116° C.                         67 -- Me Me (CH.sub.2).sub.2 Ph honey-like                                          consistency                                                             76 -- Me Me CH.sub.2 3-pyridyl 67  C.                                         77 -- Me Me CH.sub.2 2-pyridyl honey-like                                           consistency                                                             78 -- Me Me N PhCH═ 95° C.                                         83 4-Me Me Me NH Ph 179° C.                                            84 -- Me Me NH 3-Me-2-pyridyl 148° C.                                  85 4-Cl Me Me NH Ph 173° C.                                            86 3,4-(MeO).sub.2 Me Me NH Ph 165° C.                                 87 3,4-(MeO).sub.2 Me Me NH 2-Me--Ph 151° C.                           88 4-Me Me Me NH 2-Me--Ph 52° C.                                       89 4-PhO Me Me NH Ph 146° C.                                           90 4-Cl Me Me NH 3-Me-2-pyridyl 133° C.                                91 4-Cl Me Me NH 2-pyridyl 172° C.                                     93 4-PhO Me Me NH 2-Me--Ph 130° C.                                     94 4-F Me Me NH 2-Me--Ph 120° C.                                       96 4-Cl Me Me NH 2-Cl--Ph 145° C.                                      99 4-Cl H Me NH 4-Cl--Ph 163° C.                                       100 4-Cl Me Me NH 4-Cl--Ph 172° C.                                     101 4-Cl Me Me NH 4-F--Ph 170° C.                                      102 4-Cl Me Me NH 3-Cl--Ph 146° C.                                     103 4-Cl Me Me NH 4-Me--Ph 178° C.                                     105 4-Cl Me Me NH 2-Me--Ph 124° C.                                     106 4-Cl Me Me NH 3-Me--Ph 136° C.                                     107 4-F Me Me NH 3-Me--Ph 121° C.                                      108 -- Me Me NH 3-F--Ph 163° C.                                        109 -- Me Me NH 2,5-F.sub.2 --Ph 141° C.                               110 4-Me Me Me NH 4-Cl--Ph 168° C.                                     111 4-Me Me Me NH 2-Cl--Ph 168° C.                                     114 4-Me Me Me NH 3-Cl--Ph 184° C.                                     115 4-F Me Me NH 3-Cl--Ph 124° C.                                      116 4-Me Me Me NH 4-F--Ph 186° C.                                      117 4-Me Me Me NH 4-Me--Ph 157° C.                                     118 4-F Me Me NH 4-Me--Ph 158° C.                                      119 4-Me Me Me NH 3-Me--Ph 178° C.                                     121 4-F Me Me NH 4-Cl--Ph 159° C.                                      122 -- Me Me NH 2,4-(Me).sub.2 --Ph 63° C.                             123 -- Me Me NH 3-Cl-2-Pyr 127° C.                                     124 4-Cl Me Me NH 2-F--Ph 120° C.                                      125 4-F Me Me NH 2-F--Ph 112° C.                                       126 4-Me Me Me NH 2-F--Ph 156° C.                                    ______________________________________                                    

Also prepared in this manner were the following:

Compound 92, melting at 166° C. and having the formula: ##STR59##

Compound 97, melting at 158° C. and having the formula: ##STR60##

Compound 98, melting at 85° C. and having the formula: ##STR61##

Compound 104, melting at 168° C. and having the formula: ##STR62##

Compound 112, melting at 191° C. and having the formula: ##STR63##

Compound 113, melting at 174° C. and having the formula: ##STR64##

EXAMPLE 11 Preparation of4-phenyl-4-methyl-1-(phenylthio)-2-methylthio-2-imidazolin-5-one(Compound 95: M.p. 112° C.)

0.6 g (2.7 mmol) of 2-methylthio-4-methyl-4-phenyl-2-imidazolin-5-one insolution in 50 ml of anhydrous tetrahydrofuran (THF) is charged to a 100ml, three-necked, round-bottomed flask under an inert atomsphere. Thesolution is stirred with a magnetic stirrer and is cooled to 0° C. (icebath+acetone). 0.30 g (1 molar equivalent) of potassium tert-butoxide isadded and the mixture is stirred for 10 minutes at 0° C. A solutioncontaining 0.40 g of phenylsulfenyl chloride (phenylthio chloride) and10 ml of anhydrous THF is then run in. The mixture is then left toreturn to room temperature for one hour. The reaction mixture is runinto 100 ml of water. Extraction is carried out with 100 ml of ethylacetate. The organic phase is washed 4 times wtih water and dried oversodium sulfate.

The organic phase is concentrated under vacuum. A yellow honey-likeproduct is obtained which crystallizes from isopropyl ether afterpurification on silica with a yield of 68% (melting point 112° C.)

EXAMPLES OF THE PREPARATION OF COMPOUNDS OF FORMULA (I') ANDINTERMEDIATES THERETO

In the tables below, the methyl, ethyl, propyl, butyl and phenylradicals are represented respectively by Me, Et, Pr, Bu and Ph, and M.p.means melting point.

EXAMPLE 12 Preparation of a Hydrazide (XV) According to Process B(4)(a):Preparation of 2-propionylamino-2-phenyl-2'-phenylpropionohydrazide(Compound 302)

4.51 g (0.0278 mol) of N,N'-carbonyldiimidazole are added to a solution,stirred under an inert atmosphere, of 5.6 g (0.0253 mol) ofN-propionyl-2-methyl-2-phenylglycine in 150 ml of anhydrousdichloromethane and the mixture is allowed to react until gas evolutionhas ceased. 3.28 g (0.0304 mol) of phenylhydrazine are then added andthe mixture is allowed to react for 12 hours. The reaction mixture isthen concentrated under reduced pressure and the residue obtained inchromatographed on 400 g of SiO₂, the eluent being an ethylacetate/heptane (65%/35%) mixture. The advantageous fractions are thenconcentrated under reduced pressure. 4.80 (0.0154 mol) of2-propionylamino-2-phenyl-2'-phenylpropionhydrazide, melting at 144° C.,are thus recovered with a yield of 61%.

By carrying out the reaction according to the same procedure, Compounds301 to 309 and 312, collated in the following table, are obtained, whichare intermediates of Compounds 201 to 209 and 212:

    ______________________________________                                          #STR65##                                                                    No.  R.sub.1   R.sub.30 R.sub.40                                                                              Yield (%)                                                                             M.p.                                  ______________________________________                                        301  Ph        Me       Ph      53      150° C.                          302 Ph Et Ph 61 144° C.                                                303 Ph CF.sub.3 Ph 50 161° C.                                          304 Ph CCl.sub.3 Ph 49 187° C.                                         305 Ph nPr Ph 55 102° C.                                               306 Ph iPr Ph 45 130° C.                                               307 Ph tBu Ph 77 134° C.                                               308 4-Cl--Ph Me Ph 71 180° C.                                          309 4-Cl--Ph Me 2-Me--Ph 64 152° C.                                    312 Ph ClCH.sub.2 Ph 55 146° C.                                      ______________________________________                                    

EXAMPLE 13 Preparation of a Hydrazide (XV) According to Process B(4)(b):Preparation of phenylhydrazide ofN-trifluoroacetyl-2-(4-methylphenyl)glycine

1.38 g (5 mmol) of N-trifluoroacetyl-2-(4-methylphenyl)glycine, 25 ml ofanhydrous toluene and then 0.75 ml (5.5 mmol) of anhydrous triethylamineare introduced into a 100 ml round-bottomed flask. The reaction mixtureis cooled to -15° C. and then 0.475 ml (5 mmol) of ethyl chloroformateis run in dropwise. A white precipitate is then formed and stirring iscontinued at -10° C. for 30 minutes.

0.5 g (4.5 mmol) of phenylhydrazine and 25 ml of anhydrous toluene areintroduced into a vacuum flask and the mixture is cooled to -15° C.

The contents of the first round-bottomed flask are rapidly filteredthrough sintered glass into the Erlenmeyer flask containing thephenylhydrazine. The reaction mixture is allowed to return to roomtemperature, washed with dilute sodium hydroxide solution and water, andthen dried over MgSO₄ before filtering and evaporating. 1.4 g (78%yield) are thus obtained of a white solid having a melting point equalto 162° C. and having the formula: ##STR66##

EXAMPLE 14 Preparation of the Compounds of Formula (I'a) According toProcess B, by cyclization of compounds of formula (XV): Preparation of2,4-dimethyl-4-phenyl-1-phenylamino-2-imidazolin-5-one (Compound 201)

A stirred solution of 1.5 g (0.005 mol) of2-acetylamino-2-phenyl-2'-phenylpropionohydrazide and of 0.17 g (0.001mol) of paratoluenesulfonic acid in 25 ml of toluene is held at refluxfor 7 hours, the water being removed as it is formed. The reactionmixture is then concentrated under reduced pressure and the residueobtained is chromatographed on 200 g of SiO₂, the eluent being an ethylacetate/heptane (50%/50%) mixture. A thick oil is isolated whichcrystallizes by triturating with diisopropyl ether. After filtration,0.5 g (0.0018 mol) of2,4-dimethyl-4-phenyl-1-phenylamino-2-imidazolin-5-one (Compound 201) isrecovered with a yield of 36% in the form of a white powder melting at135° C.

Compounds 201 to 209 and 212 of the formula ##STR67## recorded in thefollowing table, are prepared according to the same procedure with theappropriate reactants.

    ______________________________________                                        No.  R.sub.1   R.sub.30 R.sub.40  Yield (%)                                                                            M.p.                                 ______________________________________                                        201  Ph        Me       Ph        36     135° C.                         202 Ph Et Ph 86 honey                                                         203 Ph CF.sub.3 Ph 66 104° C.                                          204 Ph CCl.sub.3 Ph 14  68° C.                                         205 Ph nPr Ph 84 honey                                                        206 Ph iPr Ph 69 122° C.                                               207 Ph tBu Ph 11  87° C.                                               208 4-Cl--Ph Me Ph 54 140° C.                                          209 4-Cl--Ph Me 2-Me--Ph 65 142° C.                                    212 Ph ClCH.sub.2 Ph 79  76° C.                                        214 Ph Et Ph 53  78° C.                                                215 Ph Et 2-Me--Ph 68 107° C.                                          216 Ph Me 2-Me--Ph 53 180° C.                                          218 Ph MeOCH.sub.2 Ph  8  95° C.                                       219 Ph MeOCH.sub.2 3-Cl--Ph 20 125° C.                                 226 4-Me--Ph Me Ph 41 142° C.                                          229 Ph MeOCH.sub.2 2-Me--Ph 54 122° C.                                 233 4-Me--Ph CF.sub.3 Ph 35 166° C.                                    245 Ph MeOCH.sub.2 2,3-diMe--Ph 55  91° C.                           ______________________________________                                    

EXAMPLE 15 Preparation of a Compound of Formula (I'a) According toProcess C(1): 2,4-dimethyl-4-phenyl-1-phenylamino-2-imidazolin-5-one(Compound 201)

A solution containing 0.9 g (4 mmol) of2,4-dimethyl-4-phenyl-2-oxazolin-5-one, 0.43 g (4 mmol) ofphenylhydrazine and 0.1 g of paratoluenesulfonic acid in 30 ml oftoluene is heated at reflux for one hour. The water formed is removed byazeotropic entrainment and the mixture is concentrated under reducedpressure. The crude product is then purified by chromatography on silicagel.

Compound 201 is thus obtained with a yield of 25%.

According to the same procedure,2,4-dimethyl-4-(4-chlorophenyl)-1-(2,3-dimethylphenylamino)-2-imidazolin-5-one(Compound 210) is obtained with a yield of 18% (M.p.: 164° C.).

EXAMPLE 16 Preparation of a Compound of Formula (I'a) According toProcess C(2):2,4-dimethyl-4-(4-chlorophenyl)-1-(2-chlorophenylamino)-2-imidazolin-5-one(Compound 211)

A solution containing 1.5 g (6.7 mmol) of2,4-dimethyl-4-(4-chlorophenyl)-2-oxazolin-5-one, 0.93 g (6.7 mmol) of2-chlorophenylhydrazine and 0.25 g of sodium acetate in 20 ml of aceticacid is heated at reflux for 2 hours. The mixture is concentrated underreduced pressure and the residues dissolved in 150 ml of methylenechloride. The methylene chloride solution is washed with an aqueousbicarbonate solution and then with pure water. The solution isconcentrated and the product purified by chromatography on silica gel,the eluent being an ethyl acetate/heptane (30%/70%) mixture.

Compound 211 is thus obtained with a yield of 43%.

Compound 213 is obtained according to the same procedure with a yield of33.5%.

The compounds of the formula: ##STR68## are obtained according to thesame procedure, which compounds are collated in the following table:

    ______________________________________                                        No.   R.sub.1   R.sub.30                                                                              R.sub.40 Yield (%)                                                                             M.p.                                 ______________________________________                                        213   4-Br--Ph  Me      Ph       34      147° C.                         217 4-Cl--Ph Ph 3-Cl--Ph 31 120° C.                                    220 Ph Me 3-Cl--Ph 43 163° C.                                          221 4-Cl--Ph Et Ph 27 144° C.                                          222 4-Br--Ph Me 2-Me--Ph 38 144° C.                                    223 4-Br--Ph Me 2-Cl--Ph 41 145° C.                                    224 4-Br--Ph Et Ph 20 110° C.                                          225 4-Cl--Ph Me iPr 53 honey                                                  230 4-F--Ph Me Ph -- 150° C.                                           231 PhCH.sub.2 Me Ph -- 192° C.                                        232 PhCH.sub.2 Et Ph -- 167° C.                                        234 Ph Me 4-iPr--Ph 20 162° C.                                         235 Ph Me 2,3-diMe--Ph 16  64° C.                                      236 Ph Me 2,3-diCl--Ph 33 165° C.                                      237 Ph Me 2,4-diMe--Ph 43 100° C.                                      238 Ph Me 3,4-diMe--Ph 30 135° C.                                      239 Ph Me 4-Cl--Ph 56  69° C.                                          240 Ph Me 2-Cl--Ph 50 196° C.                                          241 Ph Me 4-MePh 34 142° C.                                            242 Ph Me 2-MePh 45 129° C.                                            243 Ph Et 3-Cl--Ph 26  82° C.                                          244 Ph Et 2,3-diCl--Ph 41  60° C.                                      246 Ph Et 3,4-diMe--Ph 32  94° C.                                      247 Ph Et 2,3-diMe--Ph 27 109° C.                                      248 Ph Et 2,4-diMe--Ph 50  45° C.                                      249 Ph Et 4-Cl--Ph 48  73° C.                                          250 Ph Et 4-iPr--Ph 16  73° C.                                         251 Ph Et 2-Cl--Ph 56  84° C.                                          252 Ph Et 3-Me--Ph 14  85° C.                                          253 4-PhO--Ph Me Ph 54 134° C.                                         256 4-PhO--Ph Et Ph 58 honey                                                  259 3-Cl--Ph Et Ph 49 117° C.                                        ______________________________________                                    

Likewise, the spiro Compounds 227 (yield 56%, M.p.: 203° C.) and 228(yield 56%, M.p.: 153° C.) of formulae: ##STR69## are obtained.

EXAMPLE 17 Preparation According to Process E of Compounds of Formula(I'a), in which R₃₀ is a Hydrogen Atom, and of Their Intermediates ofFormula (XVI)

Part (a): 4.58 g (0.0208 mol) of methylphenylglycine acid chloridehydrochloride are added, in a single step, to a solution of 2.25 g(0.0208 mol) of phenylhydrazine in 50 ml of diethyl ether and thesuspension thus formed is left stirring for 18 hours. The suspension isfiltered and the solid is sucked dry and then redissolved in distilledwater. The solution obtained is slowly basified to pH=7-8 using asaturated sodium hydrogen carbonate solution. The precipitate thusformed is filtered and washed with distilled water and thenrecrystallized from isopropanol. After filtering the crystals and dryingunder reduced pressure at 50° C., 2 g (0.0078 mol) of(2R,2S)-2-amino-2-phenyl-2'-phenylpropionhydrazide (Compound 355),melting at 154° C. are recovered, i.e. wtih a yield of 38%.

The phenylpropionohydrazides of the formula: ##STR70## were obtainedaccording to the same procedure, which compounds are recorded in thefollowing table:

    ______________________________________                                        No.    R.sub.1                                                                             R.sub.2 R.sub.40                                                                             R.sub.5                                                                             Yield (%)                                                                            M.p.                                 ______________________________________                                        355    Ph    Me      Ph     H     38     154° C.                         357 Ph Me 2-Me--Ph H 32 115° C.                                        358 Ph Me 3-Cl--Ph H 20 164° C.                                        360 Ph Me 2-Cl--Ph H 68 112° C.                                        361 Ph Me 4-Cl--Ph H 48 177° C.                                        363 Ph Me 2-F--Ph H 43 112° C.                                         364 Ph Me 4-F--Ph H 40 142° C.                                         365 Ph Me 3-Me--Ph H 45 110° C.                                        366 Ph Me 4-Me--Ph H 26 168° C.                                        367 Ph Me 3-F--Ph H 33 161° C.                                       ______________________________________                                    

Likewise, the spiro Compound 362 [R₁ =C₆ H₄, R₂ =(CH₂)₂, R₃ =H, R₄ =Ph;yield 7% M.p.: 171° C.] is obtained.

Part (b):(4R,4S)-4-(4-fluorophenyl)-4-methyl-1-phenylamino-2-imidazolin-5-one(Compound 254):

A solution of 2.73 g (0.01 mol) of(2R,2S)-2-amino-2-(4-fluorophenyl)-2'-phenylpropionohydrazide in 16 mlof N,N-dimethylformamide dimethyl acetal is stirred for 48 hours. Thereaction mixture is concentrated under reduced pressure. The residueobtained is then chromatographed on silica, the eluent being ann-heptane/ethyl acetate mixture in the proportion: 50/50. The fractionscontaining the pure Compound 254 are concentrated together under reducedpressure. 1.5 g (0.0053 mol) of(4R,4S)-4-(4-fluorophenyl)-4-methyl-1-phenylamino-2-imidazolin-5-one,melting at 140° C. on a Kofler-type bench, are thus recovered, i.e. ayield of 53%.

The compounds of formula (I'a), in which R₃₀ is a hydrogen atom, that isto say, compounds of the formula: ##STR71## were obtained according tothis procedure, which compounds are collated in the following table:

    ______________________________________                                        No.   R.sub.1  R.sub.2  R.sub.40                                                                              Yield (%)                                                                             M.p.                                  ______________________________________                                        254   4-F--Ph  Me       Ph      53      140° C.                          255 Ph Me Ph 38 129° C.                                                257 Ph Me 2-Me--Ph 72 175° C.                                          258 Ph Me 3-Cl--Ph 46 177° C.                                          260 Ph Me 2-Cl--Ph 79 176° C.                                          261 Ph Me 4-Cl--Ph 33 153° C.                                          *262  C.sub.6 H.sub.4 (CH.sub.2).sub.2 Ph 64 202° C.                   263 Ph Me 2-F--Ph 86 151° C.                                           264 Ph Me 4-F--Ph 40 124° C.                                           265 Ph Me 3-Me--Ph 50 109° C.                                          266 Ph Me 4-Me--Ph 41 127° C.                                          267 Ph Me 3-F--Ph 20 137° C.                                         ______________________________________                                         *spiro compound                                                          

EXAMPLE OF THE PREPARATION OF COMPOUNDS OF FORMULA (I")

In the table below, the methyl, ethyl, propyl, pyridyl, acetyl andphenyl radicals are respectively represented by Me, Et, Pr, Py, Ac andPh, and M.p. means melting point.

EXAMPLE 18 Preparation of Compound 402

1.4 g (1.74 mmol) of sodium in 60 ml of ethanol is reacted, under a drynitrogen atmosphere, in a 100 ml 3-necked flask. 4 g (1.28 mmol) of4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one are thenadded. The mixture is refluxed for 6 hours, then cooled to ambienttemperature and acidified with 0.4 ml of acetic acid. The mixture isdiluted with 300 ml of ethyl acetate. The organic solution is washedwith water, then dried over magnesium sulfate and concentrated underreduced pressure: a brownish red syrup is obtained. The product ispurified by chromatography on a silica column. 1.25 g (31% yield) ofCompound 402 is obtained in the form of a slightly pinkish powdermelting at 106° C.

In the same manner, the compounds of the formula ##STR72## describedbelow have been prepared:

    ______________________________________                                        No.  (R.sub.61).sub.n                                                                          R.sub.31                                                                             R.sub.41  R.sub.51                                                                            M.p. (° C.)                    ______________________________________                                          401 -- Me Ph H 149                                                            402 -- Et Ph H 106                                                            403 -- nPr Ph H 80                                                            404 4-Cl Me Ph H 140                                                          405 -- Me 2-Me--Ph H 118                                                      406 4-Cl Me 2-pyridyl H 150                                                   408 -- Me 2-Cl--Ph H 94                                                       409 -- Me 4-Cl--Ph H 124                                                      411 3,4-di(MeO) Me Ph H 150                                                   412 4-Cl Me 4-Cl--Ph H 176                                                    413 4-Cl Me 4-F--Ph H 147                                                     414 4-Cl Me 2-Cl--Ph H syrup                                                  415 4-Cl Me 3-Cl--Ph H 147                                                    416 4-Cl Me 4-Me--Ph H 162                                                    417 4-Cl Me 3-Me--Ph H 116                                                    418 4-Me Me Ph H 110                                                          419 4-F Me Ph H 104                                                           420 4-Cl Me 2-Me--Ph H syrup                                                  421 4-F Me 3-Me--Ph H 114                                                     423 4-F Me 2-Me--Ph H 88                                                      424 4-Me Me 4-Cl--Ph H 166                                                    425 4-Me Me 3-Cl--Ph H 155                                                    427 4-Me Me 2-Cl--Ph H 86                                                     428 4-Me Me 4-F--Ph H 124                                                     429 4-F Me 3-Cl--Ph H 160                                                     430 4-Me Me 4-Me--Ph H 155                                                    431 4-F Me 4-Me--Ph H 149                                                     432 4-Me Me 2-Me--Ph H 128                                                    433 -- Me 3-F--Ph H 121                                                       434 4-Me Me 3-Me--Ph H 138                                                    435 4-PhO Me 2-Me--Ph H 120                                                   436 4-F Me 4-Cl--Ph H 142                                                     437 -- Me 4-F--Ph H 157                                                       438 -- Me 2,4-di(F)--Ph H 166                                                 439 -- Me 4-Me--Ph H 116                                                      440 4-F Me 2-F--Ph H syrup                                                    441 4-Me Me 2-F--Ph H 90                                                      442 4-Cl Me 2-F--Ph H syrup                                                   443 4-F Me 2-Cl--Ph H syrup                                                   444 -- Me 2,3-di(Me)--Ph H 140                                                445 -- Me 3-Cl-2-pyridyl H 140                                                446 -- Me 3-Me--Ph H 54                                                       447 -- Me 2-F--Ph H 136                                                       448 -- Me 3-Cl--Ph H 93                                                       449 4-F Me 3-Me-2-pyridyl H 126                                               450 4-F Me 3-F--Ph H 120                                                      451 4-Cl Me 3-F--Ph H 125                                                     452 3-Cl Me Ph H 155                                                          453 3-Cl Me 3-Me--Ph H 100                                                    454 3-Cl Me 3-Cl--Ph H 105                                                    455 3-Cl Me 3-F--Ph H 135                                                     456 3-Cl Me 2-Me--Ph H 116                                                    457 3-F Me Ph H 134                                                           458 3-F Me 3-F--Ph H 115                                                      459 -- Me Ph Ac 121                                                           460 3-F Me 3-Cl--Ph H 90                                                      461 3-Me Me Ph H 98                                                           462 3-Me Me 3-F--Ph H 118                                                     463 4-PhO Me 2-pyridyl H 146                                                  464 2,4-diF Me Ph H 163                                                       465 2,4-diF Me 3-F--Ph H 162                                                  466 4-PhO Me Ph H 114                                                         467 4-PhO Me 3-F--Ph H 56                                                     468 2-Cl Me Ph H 214                                                          469 -- Me 4-PhO--Ph H 118                                                     470 2-Cl Me 3-F--Ph H 201                                                     471 2-F Me Ph H 172                                                           472 2-F Me 3-F--Ph H 151                                                      473 2,4-diF Me 3-Cl--Ph H 130                                                 474 2-F Me 3-Cl--Ph H 151                                                     475 4-iPr Me Ph H 132                                                         476 4-PhO Me 3-Me-2-pyridyl H 142                                             477 4-iPr Me 3-F--Ph H 128                                                    478 3-Me Me 3-Cl--Ph H 115                                                    479 4-iPr Me 3-Cl--Ph H 139                                                   480 4-Br Me Ph H 138                                                          481 4-NO.sub.2 Me Ph H 143                                                    482 3-PhO Me Ph H syrup                                                       483 2,4-di(F)-4-PhO Me 3-F--Ph H 71                                           484 2,4-di(F)-4-PhO Me Ph H 76                                                485 4-F-4-PhO Me Ph H 91                                                    ______________________________________                                        Compound 407:                                                                   #STR73##                                                                      M.p. = 73° C.                                                           - Compound 410:                                                              #STR74##                                                                      M.p. = 86° C.                                                           - Compound 422:                                                              #STR75##                                                                      M.p. = 71° C.                                                           - Compound 486:                                                              #STR76##                                                                      M.p. = 98° C.                                                        ______________________________________                                    

EXAMPLES OF THE PREPARATION OF COMPOUNDS OF FORMULA (I'") ANDINTERMEDIATES THERETO

The Examples below illustrate the optically active derivatives offormula (I'") and their process of preparation.

The structures of all of the derivatives illustrated were characterizedusing at least one of the spectral techniques noted hereinabove, as wellas the usual methods for measuring optical rotations. The enantiomericexcesses were determined either by chiral phase high performance liquidchromatography or by NMR.

In the tables below, the phenyl, methyl and ethyl radicals arerepresented by Ph, Me and Et respectively. The abbreviation "c" used inconnection with optical rotation values refers to the concentration ofthe compound in the sample measured, expressed as grams per 100 ml ofsolvent.

EXAMPLE 19 Preparation of(+)-(4S)-4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one(Compound 501)

682 g (3.08 mol) of methyl(+)-(2S)-2-phenyl-2-(isothiocyanato)propionate, dissolved in 4 liters ofanhydrous tetrahydrofuran, are introduced into a 20 liter reactorthrough which passes a stream of argon. Cooling is carried out to 15° C.343 g (3.08 mol) of phenylhydrazine, dissolved in 2 liters oftetrahydrofuran, are run in over 30 minutes, the temperature beingmaintained between 15° C. and 18° C. The mixture is kept stirring for 40minutes and then cooled to 0° C. A solution of 346 g (3.08 mol) ofpotassium tert-butoxide in 4 liters of tetrahydrofuran is run in over 1hour, the temperature being maintained at 0° C. The mixture is stirredfor a further 2 hours at 0° C. and the formation of a pale-pinkprecipitate is observed. 218 ml (3.39 mol) of methyl iodide are run inover 15 minutes, the temperature being maintained between 0° C. and 3°C., and the temperature is then allowed to rise to room temperaturewhile continuing to stir for 2 hours. The reaction mixture is pouredonto 5 liters of water. After separating, the aqueous phase is extractedwith 3 times 3 liters of ethyl acetate. The combined organic phases arewashed with 5 liters of water, dried over magnesium sulfate and theconcentrated under reduced pressure. 1099 g of a brown solid areobtained. The latter is recrystallized from 2 liters of toluene.

There are obtained, after drying, 555 g(+)-(4S)-4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-onein the form of an off-white solid melting at 138° C.; yield=58%; [α]_(D)²⁷° C. =+61.1° (+ or -2.9°) (c=0.86 in ethanol); degree of enantiomericexcess (e.e) >98%.

In the same way, the following analogous compounds of formula (I'"c)were obtained:

    ______________________________________                                                                      (I'"c)                                                                          #STR77##                                         -                                                                          Compound                             M.p. Yield                                 No. R.sub.42 R.sub.62 [α].sub.D (c) Solvent (° C.)             ______________________________________                                                                                  (%)                                 501     Ph      H         +61° (0.8) EtOH                                                                   138  58                                    511 Ph 4-F +53° (0.7) EtOH 114 60                                      512 Ph 4-F (-) 114 66                                                         513 3-FPh 4-F +52° (0.7) EtOH 130 70                                   514 3-FPh 4-F (-) -- --                                                       515 Ph 4-(4-FPh)O (+) 138 45                                                  516 Ph 4-(4-FPh)O 13° (0.4) EtOH 139 71                              ______________________________________                                    

EXAMPLE 20 Preparation of(+)-(4S)-4-methyl-4-phenyl-1-phenylamino-2-thiohydantoin (Compound 507)

0.7 g (0.00316 mol) of methyl(+)-(2S)-2-isothiocyanato-2-phenylpropionate, diluted in 15 ml of drytetrohydrofuran, is introduced into a 100 ml three-necked flask under adry nitrogen atmosphere. 0.32 ml (0.00316 mol) of phenylhydrazine,diluted in 5 ml of tetrohydrofuran, is run in at 20° C. in a singlestep. The temperature rises by 2° C. The medium is kept magneticallystirring for 30 minutes. A dark-beige precipitate appears. The medium isneutralized with 0.4 ml of acetic acid and then treated with 20 ml ofwater. After separating, the aqueous phase is extracted with 3 times 20ml of ethyl ether. The organic phases are combined, washed with 2 times30 ml of water, dried over magnesium sulfate and then concentrated underreduced pressure. The solid residue obtained is chromatographed on asilica column, using an eluent mixture composed of heptane and ethylacetate in the proportions of 50/50.

0.55 g of (+)-(4S)-4-methyl-4-phenyl-1-phenylamino-2-thiohydantoin iscollected in the form of a beige solid melting at 167° C.; yield=58%;[α]_(D) ²⁷° C. =+86° (+ or -3.2°) (c=0.8 in methanol).

EXAMPLE 21 Preparation of Methyl(+)-(2S)-2-isothiocyanato-2-phenylpropionate (Compound 508)

780 g (3.61 mol) of methyl (+-(2S)-2-amino-2-phenylpropionatehydrochloride and then 3.4 liters of water are introduced into a 20liter reactor, The temperature is brought to 20° C. 3.4 liters oftoluene are added and then 911 g (10.8 mol) of sodium hydrogencarbonateare added portionwise over 1 hour. The temperature falls to 8-9° C. 276ml (3.61 mol) of thiophosgene are run in over 2 hours. The reaction isaccompanied by an evolution of gas and by a rise in temperature, whichreaches 24° C. at the end of the addition. The medium is kept stirringfor a further 2 hours. After separating, the aqueous phase is extractedwith 2 liters of toluene. The combined toluene phases are washed with 4liters of water and then dried over magnesium sulfate. The solution isconcentrated under reduced pressure.

There are obtained 682 g of methyl(+)-(2S)-2-isothiocyanato-2-phenylpropionate in the form of a slightlycolored oil; yield=85%; [α]_(D) ²⁷° C. =+16° (+ or -6.4°) (c=0.78 inchloroform).

In the same way, the following analogous compounds of formula (XIXa)were obtained:

    ______________________________________                                                                     (XIXa)                                                                          #STR78##                                       Compound                        Physical                                                                             Yield                                    No. R.sub.62 [α].sub.D (c) Solvent State (%)                          ______________________________________                                        508     H          +16° (0.78) CHCl.sub.3                                                              Oil    85                                       517 4-F (+) Oil 72                                                            518 4-F (-) Oil 80                                                            519 4-(4-FPh)O (+) Oil 61                                                     520 4-(4-FPh)O -11° (0.7) EtOH Oil 70                                ______________________________________                                    

EXAMPLE 22 Preparation of Methyl (+)-(2S)-2-amino-2-phenylpropionatehydrochloride (Compound 509)

611 g (3.7 mol) of (+)-2-aminophenylpropionic acid are charged to a 10liter reactor, to which 5 liters of methanol are added. 819 ml (11.22mol) of thionyl chloride are run onto the white suspension formed over 2hours. The temperature reaches 58° C. at the end of the addition. Asignificant evolution of gas is observed, which gas is trapped b adilute sodium hydroxide solution. The medium is heated at 65° C. for 14hours. The solution is then concentrated under reduced pressure. Thesolid obtained is treated with 1 liter of toluene, filtered and thendried under vacuum. There are obtained 762 g of methyl(+)-(2S)-2-amino-2-phenylpropionate hydrochloride in the form of a whitepowder melting at 162° C.; yield=62%; [α]_(D) ²⁹° C. =+53.3° (+ or-3.3°) (c=0.75 in water).

In the same way, the following analogous compounds of formula (XXIIa)were obtained:

    ______________________________________                                                                     (XXIIa)                                                                         #STR79##                                       Compound                       Physical                                                                            M.p. Yield                                 No. R.sub.62 [α].sub.D (c) Solvent State (° C.) (%)            ______________________________________                                        509     H         +54° (0.91) CHCl.sub.3                                                              white 162  62                                       crystals                                                                   521 4-F +61° (0.9) EtOH white 50- 93                                      solid 60                                                                   522 4-F (-) white -- 95                                                          solid                                                                      523 4-(4-FPh)O (+) white -- 87                                                   solid                                                                      524 4-(4-FPh)O (-) white -- 95                                                   solid                                                                    ______________________________________                                    

Methyl (+)-(2S)-2-amino-2-phenylpropionate is obtained by treating thehydrochloride prepared above with one equivalent of sodiumhydrogencarbonate and then extracting with dichloromethane. It exists inthe form of a colorless, slightly viscous oil; ##EQU1## in chloroform),e.e >95%.

EXAMPLE 23 Preparation of(+)-(4S)-4-methyl-2-methoxy-4-phenyl-1-phenylamino-2-imidazolin-5-oneCompound 503)

80 ml of methanol and then 0.74 g (0.032 mol) of sodium, cut into thinpieces, are introduced into a 250 ml, three-necked, round-bottomed flaskunder a dry nitrogen atmosphere. 5 g (0.016 mol) of(+)-(4S)-4-methyl-2-methylthio-4-phenyl-1-phenylamino-2imidazolin-5-oneare then added. The mixture is brought to reflux for 20 hours. Themixture is cooled to room temperature and then acidified with 0.5 ml ofacetic acid. The methanol is removed by distillation under reducedpressure and the residue obtained is then taken up in 50 ml of ethylether, washed with 3 times 40 ml of water, dried over magnesium sulfateand then the solution is concentrated under reduced pressure. A reddishhoney is obtained which is purified by chromatography on a silica columnwith a 70/30 heptane/ethyl acetate mixture as eluent.

2 g of(+)-(4S)-4-methyl-2-methoxy-4-phenyl-1-phenylamino-2-imidazolin-5-oneare obtained in the form of a pale-pink melting at 132° C.; yield=42%;##EQU2## (+ or -2.4°) (c=1 in methanol); e.e. >98%.

In the same way, the following analogous compounds of formula (I'"d)were obtained:

    ______________________________________                                                                      (I'"d)                                                                          #STR80##                                         -                                                                          Compound                            M.p.  Yield                                 No. R.sub.42 R.sub.62 [α].sub.D (c) Solvent (° C.)             ______________________________________                                                                                  (%)                                 503     Ph      H         +53° (1.0) MeOH                                                                  132   42                                    525 Ph 4-F +34° (0.5) 129 66                                           526 Ph 4-F -33° (0.5) EtOH 129 66                                      527 3-FPh 4-F +29° (0.5) EtOH 130 43                                   528 3-FPh 4-F (-) -- --                                                       529 Ph 4-(4-FPh)O (+) glass 25                                                530 Ph 4-(4-FPh)O -12° (0.4) EtOH glass 44                           ______________________________________                                    

EXAMPLE 24 Preparation of (+)-(2S)-2-amino-2-phenylpropionic Acid(Compound 510)

22 g (0.115 mol) of (+)-(5S)-5-methyl-5-phenylhydantoin, 100 ml of waterand 100 ml of 28% aqueous ammonia are introduced successively into a 1liter autoclave. The medium is heated at 160° C. for 15 hours. Aftercooling to room temperature, the solution is concentrated under reducedpressure. The white solid obtained is treated with 100 ml of ethylacetate for 2 hours and then filtered and dried under vacuum at 80° C.

10.5 g of (+)-(2S)-2-amino-2-phenylpropionic acid are collected in theform of a white powder which has a decomposition temperature of 266° C.;yield=55%; ##EQU3## in 1 N hydrochloric acid).

In the same way, the following analogous compounds of formula (XXIa)were obtained:

    ______________________________________                                                                     (XXIa)                                                                          #STR81##                                       Compound                         M.p.  Yield                                    No. R.sub.62 [α].sub.D (c) Solvent (° C.) (%)                  ______________________________________                                        510      H          +72° (0.8) 1N HCl                                                                   266   55                                       531 4-F (+) -- 44                                                             532 4-F (-) -- 92                                                             533 4-(4-FPh)O (+) -- 87                                                      534 4-(4-FPh)O (-) -- 76                                                    ______________________________________                                    

Example 25 illustrates the preparation of the compounds of formula(XXVII).

EXAMPLE 25 Preparation of (+)-(5S)-5-methyl-5-phenylhydantoin (Compound535)

5.6 g (0.139 mol) of sodium hydroxide are added to a stirred suspensionof 70.0 g (0.368 mol) of (5R,5S)-5-methyl-5-phenylhydantoin in 2000 mlof water. The solution obtained is brought to 40° C. and then 44.6 g(0.368 mol) of (+)-R-α-methylbenzylamine are added. The solutionobtained is maintained at 50° C. for 0.75 hour and a white precipitateappears after 3 minutes. On completion of heating, the reaction mediumis allowed to crystallize for 24 hours, the crystals are then filtered,washed with 70 ml of water and pulled dry under an air stream for 2hours. There are recovered 45 g of a white solid which is added to 220ml of 1 N hydrochloric acid at 10° C. The suspension obtained is stirredfor 2 hours, the crystals are then filtered, washed with 100 ml of waterand pulled dry and then dried under reduced pressure at 50° C. for 15hours. There are thus recovered 23 g (0.121 mol) of(+)-(5S)-5-methyl-5-phenylhydantoin in the form of an off-white solidmelting at 242° C.; yield=66%; ##EQU4## (c=1.0 in ethanol).

In the same way, by using (-)-S-α-methylbenzylamine,(-)-(5R)-5-methyl-5-phenylhydantoin is recovered in the form of anoff-white solid melting at 248° C.; yield=54%; ##EQU5## (c=1.0 inethanol).

In the same way, the following analogous compounds of formula (XXVIIa)were obtained:

    ______________________________________                                                                    (XXVIIa)                                                                        #STR82##                                        Compound                         M.p.  Yield                                    No. R.sub.62 [α].sub.D (c) Solvent (° C.) (%)                  ______________________________________                                        535      H          +113° (1.0) EtOH                                                                    242   66                                       536 H -120° (1.0) EtOH 248 54                                          537 4-F +111° (0.8) EtOH 230 44                                        538 4-F -114° (0.8) EtOH 230 31                                        539 4-(4-FPh)O  +54° (0.5) EtOH 190 --                                 540 4-(4-FPh)O  -57° (0.6) EtOH 189 40                               ______________________________________                                    

The Examples below illustrate the optically active derivatives offormula (I'") obtained according to Variant B of the process ofpreparation.

EXAMPLE 26 Separation of the (+) and (-) Enantiomers of the Compound ofthe Following Formula (Compounds 501 and (502) ##STR83##

The corresponding racemic compound is prepared according to a procedureanalogous to that described in Example 1 hereinabove. This racemiccompound is dissolved in an eluent mixture composed of n-heptane,isopropanol and dichloromethane, in the respective portion by weight of93, 5 and 2%.

2.3 ml of the mixture thus obtained are injected into the chiral, highperformance chromatographic column with the following characteristics:

column of Pirkle type, with a diameter of 10 mm and a length of 250 mm;

support: 5 μm 100 angstrom silica containing ionic D-phenylglycinegrafts.

The flow rate chosen is 10 ml/minute and the detector used is a UVdetector at 250 nm. The enantiomerically pure compounds are recovered byfractionation and concentration of the pure fractions.

The physical characteristics of the enantiomers obtained, namely themelting point M.p., the optical rotation ##EQU6## measured in degreesfor the compound dissolved in ethanol at a concentration of 0.5 g per100 ml, and the retention time t_(R), have been collated in the tablebelow:

    ______________________________________                                        Compound                         t.sub.R                                        No. M.p. (° C.) [α].sub.D.sup.20 (in minutes)                  ______________________________________                                        501     138          +60.7 + or -1.3                                                                           5.73                                           502 138 -59.6 + or -0.9 6.55                                                ______________________________________                                    

EXAMPLE 27 Separation of the (+) and (-) Enantiomers of the Compound ofthe Following Formula (Compounds 503 and 504) ##STR84##

The corresponding racemic compound is prepared according to a procedureanalogous to that described in Example 18 hereinabove. The corresponding(+) and (-) enantiomers (Compounds 503 and 504, respectively) areobtained by carrying out the separation in the same way as above. Thevolume injected into the chiral column is 1.5 ml. The optical rotationis measured after dissolving the compounds in methanol and appears withthe other physical characteristics, identical to those determined above,in the table below.

    ______________________________________                                        Compound                         t.sub.R                                        No. M.p. (° C.) [α].sub.D.sup.20 (in minutes)                  ______________________________________                                        503     132          +51.3 + or -1.2                                                                           9.89                                           504 132 -53.2 + or -1.3 11.17                                               ______________________________________                                    

EXAMPLE 28 Separation of the (+) and (-) Enantiomers of the Compound ofthe Following Formula (Compounds 505 and 506) ##STR85##

The corresponding racemic compound is prepared according to a procedureanalogous to that described in Example 18 hereinabove. The corresponding(+) and (-) enantiomers (Compounds 505 and 506, respectively) areobtained by carrying out the separation in the same way as above. Theresults obtained are collated in the table below:

    ______________________________________                                        Compound                                                                              M.p.                          Absolute                                  No. (° C.) [α].sub.D.sup.20 (c) Solvent Configuration          ______________________________________                                        505     202     +32.3°                                                                         (c = 0.5)                                                                            MeOH   S                                         506 202  32.2° (c = 0.5) MeOH R                                      ______________________________________                                    

The absolute configuration of Compounds 501 to 504 was determined bychemical correlation with the absolute configuration of thecorresponding α-amino acid described in the literature. The absoluteconfiguration of Compounds 505 and 506 was determined by X-raycrystallography.

EXAMPLES OF THE ANTIFUNGAL PROPERTIES OF COMPOUNDS OF THE INVENTIONEXAMPLE 29

In vitro test of compounds of formula (I):

The action of the compounds of formula (I) according to the invention isstudied on the following fungi responsible for diseases of cereals andother plants:

Fusarium oxysporum f.sp.melonis

Rhizoctonia solari AG4

Helminthosporium gramineum

Pseudocercosporella herpotrichoides

Alternaria alternata

Septoria nodorum

Fusarium roseum

Pythium rostratum

Pythium vexans

Each test is carried out in the following way: a nutrient mediumconsisting of potato, glucose and gelose (PDA medium) is introduced inthe supercooled state into a series of Petri dishes (100 ml per dish)after sterilization in an autoclave at 120° C.

While filling the dishes, an acetone solution of the active material isinjected into the supercooled medium to obtain the desired finalconcentration.

The controls consist of Petri dishes analogous to the above which havebeen charged with similar quantities of a nutrient medium which does notcontain active material.

After 24 hours, each dish is cultured by depositing a fragment of groundmycelium arising from a previous culture of the same fungus.

The dishes are stored for 5 days at 20° C. and the growth of the fungusin the dishes containing the active material to be tested is thencompared with that of the same fungus in the dish used as the control.

For each compound tested, the degree of inhibition of the fungus studiedis thus determined for a dose of 20 ppm.

The following results are then obtained:

A good activity, that is to say a degree of inhibition of the fungus ofbetween 80% and 100%, was found for the following compounds of formula(I):

Compounds 9, 13, 16, 22, 26 and 34 for Pythium rostratum and Pythiumvexans;

Compound 26 for Fusarium oxysporum and Fusarium roseum;

Compounds 11, 16, 22 and 26 for Alternaria alternata;

Compounds 11, 16 and 26 for Rhizoctonia solari;

Compounds 16 and 26 for Pseudocercosporella herpotrichoides;

Compounds 11, 16 and 26 for Septoria nodorum; and

Compounds 9, 11, 16 and 26 for Helminthosporium gramineum.

EXAMPLE 30

In vivo test on Plasmopara viticola (grape downy mildew) of compounds offormulae (I), (I') and (I")

An aqueous suspension of the active material to be tested is prepared,by fine milling, having the following composition:

active material: 60 mg

Tween 80 surface-active agent (oleate of polyoxyethylenated derivativeof sorbitan) diluted to 10% in water: 0.3 ml

volume made up to 60 ml with water.

This aqueous suspension is then diluted with water to produce thedesired concentration of active material.

Vine cuttings (Vitis vinifera), Chardonnay variety, are grown in pots.When these plants are 2 months old (8-10-leaf stage, height of 10 to 15cm), they are treated by spraying with the above aqueous suspension.

Plants used as controls are treated with an aqueous solution which doesnot contain the active material.

After drying for 24 hours, each plant is infected, by spraying, with anaqueous suspension of spore of Plasmopara viticola obtained from a 4-5day culture, and then suspended at a concentration of 100,000 units percm³.

The infected plants are then incubated for two days at approximately 18°C. in an atomsphere saturated with moisture and then for 5 days atapproximately 20-22° C. under 90-100% relative humidity.

Reading is carried out 7 days after infecting, by comparison with thecontrol plants.

Under these conditions, a good (at least 75%) or complete protection isobserved, at a dose of 1 g/l, with the following compounds of formula(I): 1, 2, 9, 10, 12, 13, 15, 16, 18, 20, 22, 23, 24, 25, 30, 31, 34,35, 37, 39 to 43, 45, 48, 55 to 58, 60, 62, 64, 68, 73, 75, 76, 83 to85, 88 to 91, 93 to98, 101 to 108.

Under these conditions, a good (at least 75%) or complete protection isalso observed, at a dose of 1 g/l, with the following compounds offormula (I'): 201, 202, 203, 213, 215 to 218, 220 to 222, 224, 226 to230, 235, 237 to 257, 259 to 262, 264 to 267.

Also under these conditions, a good (at least 75%) or total protectionis seen at a dose of 1 g/l with the following compounds of formula (I"):401, 403 to 421, 423 to 425, 427 to 481, 483, 484 and 486.

EXAMPLE 31 In vivo test on Puccinia recondita (brown rust of wheat) ofcompounds of formulae (I), (I') and (I")

An aqueous suspension of the active material to be tested is prepared,by fine milling, having the following composition:

active material: 60 mg

Tween 80 surface-active agent (oleate of polyoxyethylenated derivativeof sorbitan) diluted to 10% in water: 0.3 ml

volume made up to 60 ml with water.

This aqueous suspension is then diluted with water to produce thedesired concentration of active material.

Wheat, in pots, sown on a 50/50 peat/pozzolana earth substrate, istreated at the 10 cm high state by spraying the above aqueoussuspension.

After 24 hours, an aqueous suspension of spores (100,000 sp/cm³) ofPuccinia recondita is sprayed on the wheat; this suspension was obtainedfrom infected plants. The wheat is then placed for 24 hours in anincubation cell at approximately 20° C. and at 100% relative humidity,and then for 7 to 14 days at 60% relative humidity.

Monitoring of the condition of the plants is carried out between the 8thand 15th day after infection, by comparison with an untreated control.

Under these conditions, a good (at least 75%) or complete protection isobserved, at a dose of 1 g/l, with the following compounds of formula(I): 2, 9, 10, 15, 18, 20 to 22, 39, 55, 57, 64, 68, 75, 83 to 85, 88 to90, 93, 94 and 98.

Under these conditions a good (at least 75%) or complete protection isobserved, at a dose of 1 g/l, with the following compounds of formula(I'): 201, 202, 203, 208, 212, 217, 221, 222, 224, 228, 230, 235, 253,254, 256 and 259.

Also under these conditions, good (at least 75%) or total protection isseen, at a dose of 1 g/l, with the following compounds of formula (I"):401, 404 to 410, 414, 415, 419 to 421, 423, 425, 427 to 429, 431 to 433,436, 437, 439, 440 to 448, 450 to 455, 457, 458, 460, 461, 463 to 467,469, 471 to 480, 482 to 484 and 486.

EXAMPLE 32 In vivo test on Phytophthora infestans (tomato late blight)of compounds of formulae (I), (I') and (I")

An aqueous suspension of the active material to be tested is prepared,by fine milling, having the following composition:

active material: 60 mg

Tween 80 surface-active agent (oleate of polyoxyethylenated derivativeof sorbitan) diluted to 10% in water: 0.3 ml

volume made up to 60 ml with water.

This aqueous suspension is then diluted with water to produce thedesired concentration of active material.

Tomato plants (Marmande variety) are grown in pots. When these plantsare one month old (5 to 6-leaf stage, 12 to 15 cm high), they aretreated by spraying the above aqueous suspension at variousconcentrations of the compound to be tested.

After 24 hours, each plant is infected by spraying with an aqueoussuspension of spores (30,000 sp/cm³) of Phytophthora infestans.

After this infecting, the tomato plants are incubated for 7 days atapproximately 20° C. in an atmosphere saturated with moisture.

Seven days after infecting, the results obtained in the case of theplants treated with the active material to be tested are compared withthose obtained in the case of the plants used as controls.

Under these conditions, a good (at least 75%) or complete protection isobserved, at a dose of 1 g/l, with the following compounds of formula(I): 2, 9, 15, 30, 39, 45, 55, 68, 75, 84, 85, 90, 94, 98, 107 and 108.

Under these conditions, a good (at least 75%) or complete protection isalso observed, at a dose of 1 g/l, with the following compounds offormula (I'): 201, 202, 213, 218, 221, 224, 249, 254.

Also under these conditions a good (at least 75%) or total protection isseen, at a dose of 1 g/l, with the following compounds of formula (I"):401, 404 to 410, 415, 418 to 421, 423, 428, 429, 431 to 433, 436, 437,439, 442 to 444, 446 to 455, 457, 458, 460 to 467, 472 to 474, 481, 484and 486.

These results clearly show the good fungicidal properties of thederivatives of formulae (I), (I') and (I") according to the inventionagainst fungal diseases of plants due to fungi belonging to the mostdiverse families, such as the Phycomycetes, Basidiomycetes, Ascomycetes,Adelomycetes or Fungi Imperfecti, in particular grape downy mildew,tomato late blight and brown rust of wheat.

EXAMPLE 33

In vivo test on Pyricularia oryzae (blast disease of rice) of compoundsof formula (I")

An aqueous suspension is prepared, by fine grinding, of the activesubstance to be tested having the following composition:

active substance: 60 mg

surface-active agent (oleate of polyoxyethylene derivative of sorbitan)diluted to 10% in water: 0.3 ml

water: quantity sufficient to make 60 ml.

This aqueous suspension is then diluted with water to obtain the desiredconcentration of active substance.

Rice, sown in pots in a 50:50 mixture of enriched peat and pozzolana, istreated at the approximately 10 cm height stage (which corresponds tothe 2-3 leaf stage) by spraying with the aqueous suspension above.

After 24 hours, an aqueous suspension of spores of Pyricularia oryzae,obtained from a culture of 15 days and then suspended at a rate of100,000 units per cm³, is applied to the leaves.

The rice plants are incubated for 24 hours (25° C., 100% relativehumidity), then put in an observation chamber, under the sameconditions, for 5 days.

Reading takes place 6 days after contamination.

Under these conditions, good (at least 75%) or total protection is seen,at a dose of 1 g/l, with the following compounds of formula ("): 401,404 to 407, 417, 419, 420, 423, 425, 429, 431 to 433, 435, 440 to443,446, 447, 450, 452, 454, 455, 457, 459, 461, 463 to 467, 471, 472,474, 478, 482, 484 and 485.

EXAMPLE 34 In vivo test on Septoria tritici (leaf spot of wheat) ofcompounds of formula (I")

An aqueous suspension, of concentration 1 g/l, of the active substancetested is obtained by grinding 60 mg of the latter in the followingmixture:

acetone: 5 ml

surface-active agent (oleate of polyoxyethylene derivative of sorbitan)diluted to 10%: 0.3 ml, then the volume is adjusted to 60 ml with water.

This aqueous suspension is then diluted with water to obtain the desiredconcentration of active substance.

Wheat plants (Darius variety), sown on a 50:50 peat-pozzolana substrateand grown under glass at a temperature of 10-12° C., are treated at the1 leaf stage (height of approximately 10 cm) by spraying with thesuspension of active substance described above.

Some plants, used as controls, are treated by spraying with the anaqueous solution which does not contain the active substance.

24 hours after treatment, the plants are contaminated by spraying withan aqueous suspension of spores (500,000 spores/ml) of Septoria triticicollected in a 7 day-old culture.

After contamination, the plants are placed in a humid atmosphere at 18°C. Marking is carried out 20 days after contamination in comparison withthe control plants.

Under these conditions, good (at least 75%) or total protection is seen,at a dose of 1 g/l, with the following compounds of formula (I"): 401,404 to 406, 409, 419, 420, 423, 432, 433, 435 to 437, 440, 442 to 445,447, 448, 450, 452, 454, 455, 457, 458, 460, 462 to 464, 466, 467, 471to 480, 483, 484 and 486.

These results clearly show the good fungicidal properties of thederivatives of formula (I") according to the invention againstadditional fungal diseases of plants, in particular leaf spot of wheatand also blast disease of rice.

The following Examples illustrate the fungicidal properties of Compounds501 to 506, 511 to 514 and 525 to 528 of formula (I"') according to theinvention. In these Examples, the racemic modification corresponding toenantiomeric Compounds 501 and 502 is recorded as 501+502. Likewise, theracemic modification corresponding to Compounds 503 and 504 is recordedas 503+504. More generally, the racemic modification corresponding toenantiomeric Compounds n and n+1 is recorded as n+(n+1).

EXAMPLE 35 In vivo comparative test on Puccinia recondita (brown rust ofwheat) of compounds of formula (I"'):

An aqueous suspension of the active material to be tested is prepared,by fine milling, having the following composition:

active material: 60 mg

Tween 80 surface-active agent (oleate of polycondensate of ethyleneoxide with sorbitan) diluted to 10% in water: 0.3 ml

volume made up to 60 ml with water.

The active material to be tested is either one of the two enantiomers offormula (I'") according to the invention or the corresponding racemicmodification.

This aqueous suspension is then diluted with water to produce thedesired concentration of active material.

Wheat of the Talent variety, in pots, sown on a 50/50 peat/pozzolanaearth subtrate, is treated at the 10 cm high stage by spraying the aboveaqueous suspension.

After 24 hours, an aqueous suspension of spores (100,000 sp/cm³) ofPuccinia recondita is sprayed on the wheat; this suspension was obtainedfrom infected seedlings. The wheat is then placed for 24 hours in anincubation cell at approximately 20° C. and at 100% relative humidity,and then for 7 to 14 days at 60% relatively humidity.

Monitoring of the condition of the seedlings is carried out between the8th and 15th day after infection, by comparison with an untreatedcontrol. The concentration of active material tested, IC₇₅ (expressed inppm), at which 75% inhibition of the disease is observed, is thendetermined.

The results are collated in the following table:

    ______________________________________                                        Compound No.   IC.sub.75 (ppm)                                                ______________________________________                                        501 + 502      330                                                              501 37                                                                        502 >1000                                                                     503 + 504 330                                                                 503 110                                                                       504 >1000                                                                     505 + 506 330                                                                 505 110-330                                                                   506 >1000                                                                     511 + 512  37-110                                                             511 12-37                                                                     512 --                                                                        513 + 514 37                                                                  513 12                                                                        514 --                                                                        525 + 526 12                                                                  525 --                                                                        526 >1000                                                                     527 + 528 37                                                                  527  4                                                                        528 --                                                                      ______________________________________                                    

EXAMPLE 36 In vivo comparative test on Phytophthora infestans (tomatolate blight) of compounds of formula (I'")

An aqueous suspension of the active material to bested is prepared, byfine milling, having the following composition:

active material: 60 mg

Tween 80 surface-active agent (oleate of polycondensate of ethyleneoxide with sorbitan) diluted to 10% in water: 0.3 ml

volume made up to 60 ml with water.

The active material to be tested is chosen from the same compounds as inthe preceding example.

This aqueous suspension is ten diluted with water to produce the desiredconcentration of active material.

Tomato seedlings (Marmande variety) are grown in pots. When theseseedlings are one month old (5 to 6-leaf stage, 12 to 15 cm high), theyare treated by spraying the above aqueous suspension at variousconcentrations of the compound to be tested.

After 24 hours, each seedling is infected by spraying with an aqueoussuspension of spores (30,000 sp/cm³) of Phytophthora infestans.

After this infecting, the tomato seedings are incubated for 7 days atapproximately 20° C. in an atmosphere saturated with moisture.

Seven days after infecting, the results obtained in the case of theseedlings treated with the active material to be tested are comparedwith those obtained in the case of the seedlings used as controls. Theconcentration of active material tested, IC₇₅ (expressed in ppm), atwhich 75% inhibition of the disease is observed, is then determined.

The results are collated in the following table:

    ______________________________________                                        Compound No.   IC.sub.75 (ppm)                                                ______________________________________                                        501 + 502      110                                                              501  37                                                                       502 >1000                                                                     503 + 504 330                                                                 503 110                                                                       504 >1000                                                                     505 + 506 >1000                                                               505  37                                                                       506 >1000                                                                     511 + 512 110                                                                 511 12-37                                                                     512 --                                                                        513 + 514 110                                                                 513  37                                                                       514 --                                                                        525 + 526 110                                                                 525  37                                                                       526 >1000                                                                     527 + 528  37                                                                 527  4-12                                                                     528 --                                                                      ______________________________________                                    

In one preferred aspect, the present invention also relates to thecompositions for protecting plants against fungal diseases, comprising,in combination with one or more solid or liquid vehicles which areacceptable in agriculture and/or surface-active agents which are alsoacceptable in agriculture, one (or a number of) active material which isa compound of formula (I"'). Preferably, the active material of formula(I"') consists of the optically pure enantiomer which has the greaterfungicidal activity, or contains the enantiomer having the greaterfungicidal activity in greatly enriched form (as defined hereinabove).

In fact, generally speaking, for their practical use the compoundsaccording to the invention, i.e. the compounds of formulae (I), (I'),(I") and (I"'), are rarely used on their own. Most often these compoundsform part of compositions. These compositions, which can be used asfungicidal agents, contain, as active material or active substance, acompound according to the invention as described above as a mixture withsolid or liquid vehicles or supports which are acceptable in agricultureand surface-active agents which are also acceptable in agriculture. Inparticular, the customary inert vehicles or supports and the customarysurface-active agents can be used. These compositions also form part ofthe invention.

These compositions can also contain all kinds of other ingredients suchas, for example, protective colloids, adhesive, thickening agents,thixotropic agents, penetration agents, stabilitizing agents,sequestering agents and the like. More generally, the compounds used inthe invention can be used in combination with any of the solid or liquidadditives which correspond to the usual formulating techniques.

Generally, the compositions according to the invention usually containapproximately 0.05 to 95% (by weight) of a compound according to theinvention, i.e. a compound of formula (I), (I'), (I") or (I"')(subsequently called "active material" or "active substance"), one ormore solid or liquid vehicles or supports and, optionally, one or moresurface-active agents.

The term "vehicle" or "support", in the present account, means a naturalor synthetic, organic or inorganic material with which the compound iscombined in order to facilitate its application to the plant, to seedsor to the soil. This vehicle is therefore generally inert and its has tobe acceptable in agriculture, especially to the treated plant. Thevehicle can be solid (clays, natural or synthetic silicates, silica,resins, waxes, solid fertilizers, and the like) or liquid (water,alcohols, especially butanol, and the like).

The surface-active agent can be an emulsifying, dispersing or wettingagent of ionic or nonionic type or a mixture of such surface-activeagents. There may be cited, for example, salts of poly(acrylic acids),salts of lignosulfonic acids, salts of phenolsulfonic ornaphthalenesulfonic acids, polycondensates of ethylene oxide with fattyalcohols or fatty acids or fatty amines, substituted phenols (especiallyalkylphenols or arylphenols), salts of esters of sulfosuccinic acids,derivatives of taurine (especially alkyltaurates), phosphoric esters ofpolycondensates of ethylene oxide with alcohols or phenols, esters offatty acids and of polyols, and the derivatives of the above compoundshaving sulfate, sulfonate or phosphate functional groups. The presenceof at least one surface-active agent is generally indispensable wherethe compound and/or the inert vehicle are/is not soluble in water andwhere the vector agent of the application is water.

Thus, the compositions for agricultural use according to the inventioncan contain the active materials according to the invention within verywide limits, ranging from 0.05% to 95% (by weight). Their surface-activeagent content is advantageously between 5% and 40% by weight.

These compositions according to the invention are themselves in fairlydiverse, solid or liquid forms.

There may be mentioned, as solid composition forms, powders for dusting(containing the compound at a content of up to 100%) and granules,especially those obtained by extrusion, by compacting, by impregnationof a granulated vehicle, or by granulation from a powder (the content ofthe compound in these granules being between 0.5 and 80% for the lattercases), tablets/pills or effervescent tablets.

The compounds of formulae (I), (I'), (I"), and (I"') can also be used inthe form of powders for dusting; it is also possible to use acomposition comprising 50 g of active material and 950 g of talc; it isalso possible to use a composition comprising 20 g of active material,10 g of finely divided silica and 970 g of talc; these constituents aremixed and milled and the mixture is applied by dusting.

As composition forms which are liquid or intended to constitute liquidcompositions during application, there may be mentioned solutions, inparticular water-soluble concentrates, emulsifiable concentrates,emulsions, suspension concentrates, aerosols, wettable powders (orsprayable powders), pastes or gels.

The emulsifiable or soluble concentrates more often comprise 10 to 80%of active material, while the ready-to-apply solutions or emulsionscontain 0.001 to 20% of active material.

In addition to the solvents, the emulsifiable concentrates can contain,when this is necessary, 2 to 20% of suitable additives such as thestabilizing agents, surface-active agents, penetration agents, corrosioninhibitors, dyes or adhesives mentioned above.

It is possible, by diluting these concentrates with water, to obtainemulsions of any desired concentration which are particularly suitablefor application to crops.

By way of example, the compositions of several emulsifiable concentrateswill now be given:

                  EXAMPLE EC1                                                     ______________________________________                                        active material       400 g/l                                                   alkaline dodecylbenzenesulfonate  24 g/l                                      condensate of 10 molecules of ethylene  16 g/l                                oxide with nonylphenol                                                        cyclohexanone 200 g/l                                                         aromatic solvent q.s. 1 liter                                               ______________________________________                                    

According to another emulsifiable concentrate formula, there are used:

                  EXAMPLE EC2                                                     ______________________________________                                        active material       250 g                                                     epoxidized vegetable oil  25 g                                                mixture of alkylarylsulfonate and of 100 g                                    ether of polyglycol and fatty alcohols                                        dimethylformamide  50 g                                                       xylene 575 g                                                                ______________________________________                                    

The suspension concentrates, which can also be applied by spraying, areprepared so as to produce a stable fluid product which does not settleout and they generally contain from 10 to 75% of active material, from0.5 to 15% of surface-active agents, from 0.1 to 10% of thixotropicagents, from 0 to 10% of suitable additives, such as antifoaming agents,corrosion inhibitors, stabilizing agents, penetration agents andadhesives and, as vehicle or support, water or an organic liquid inwhich the active material has little or no solubility: certain solidorganic materials or inorganic salts can be dissolved in the vehicle tohelp in preventing sedimentation or as antifreeze for the water.

By way of example, the composition of a suspension concentrate will nowbe given:

                  EXAMPLE SC1                                                     ______________________________________                                        active material       500 g                                                     polycondensate of ethylene oxide with 50 g                                    tristyrylphenyl phosphate                                                     polycondensate of ethylene oxide with 50 g                                    alkylphenol                                                                   sodium polycarboxylate 20 g                                                   ethylene glycol 50 g                                                          organopolysiloxane oil (antifoam)  1 g                                        polysaccharide 1.5 g                                                          water 316.5 g                                                               ______________________________________                                    

The wettable powders (or sprayable powders) are generally prepared sothat they contain 20 to 95% of active material, and they generallycontain, in addition to the solid vehicle, from 0 to 30% of a wettingagent, from 3 to 20% of a dispersing agent and, when necessary, from 0.1to 10% of one or more stabilizing agents and/or other additives, such aspenetration agents, adhesives, or anticaking agents, dyes, and the like.

In order to obtain the sprayable powders or wettable powders, the activematerials are intimately mixed in suitable mixers with the additionalsubstances and the mixture is milled in mills or other suitablegrinders. Sprayable powders are thereby obtained whose wettability andsuspensibility are advantageous; they can be suspended in water at anydesired concentration and these suspensions can be used veryadvantageously, in particular, for application to plant leaves.

Instead of wettable powders, it is possible to produce pastes. Theconditions and method for producing and using these pastes are similarto those for the wettable powders or sprayable powders.

By way of example, various wettable powder (or sprayable powder)compositions will now to be given:

                  EXAMPLE WP1                                                     ______________________________________                                        active material        50%                                                      condensate of ethylene oxide with fatty 2.5%                                  alcohol (wetting agent)                                                       condensate of ethylene oxide with   5%                                        phenylethylphenol (dispersing agent)                                          chalk (inert vehicle) 42.5%                                                 ______________________________________                                    

    ______________________________________                                        active material          10%                                                    condensate of 8 to 10 mol of ethylene 0.75%                                   oxide with C.sub.13 branched-type synthetic                                   oxo alcohol (wetting agent)                                                   neutral calcium lignosulfonate 12%                                            (dispersing agent)                                                            calcium carbonate (inert filler) q.s. 100%                                  ______________________________________                                    

EXAMPLE WP3

This wettable powder contains the same ingredients as in the aboveExample, in the proportions below:

    ______________________________________                                        active material          75%                                                    wetting agent 1.50%                                                           dispersing agent 5%                                                           calcium carbonate (inert filler) q.s. 100%                                  ______________________________________                                    

    ______________________________________                                        active material          90%                                                    condensate of ethylene oxide with fatty 4%                                    alcohol (wetting agent)                                                       condensate of ethylene oxide with 6%                                          phenylethylphenol (dispersing agent)                                        ______________________________________                                    

    ______________________________________                                        active material          50%                                                    mixture of anionic acid nonionic surface- 2.5%                                active agents (wetting agent)                                                 sodium lignosulfonate (dispersing agent) 5%                                   kaolin clay (dispersing vehicle) 42.5%                                      ______________________________________                                    

The aqueous dispersions and emulsions, for example, the compositionsobtained by diluting a wettable powder or an emulsifiable concentrateaccording to the invention using water, are included within the generalscope of the present invention. The emulsions can be of water-in-oil oroil-in-water type and they have a thick consistency like that of a"mayonnaise".

The compounds according to the invention can be formulated in the formof water-dispersible granules also included in the scope of theinvention.

These dispersible granules, with an apparent density generally betweenapproximately 0.3 and 0.6, have a particle size generally betweenapproximately 150 and 2,000 and preferably between 300 and 1,500microns.

The active material content of these granules is generally betweenapproximately 1% and 90%, and preferably between 25% and 90%.

The remainder of the granule is essentially composed of a solid fillerand optionally of surface-active adjuvants which conferwater-dispersibility properties on the granule. These granules can beessentially of two distinct types depending upon whether the filler usedis soluble on insoluble in water. When the filler is water-soluble, itcan be inorganic or, preferably, organic. Excellent results have beenobtained with urea. In the case of an insoluble filler, the latter ispreferably inorganic, such as, for example, kaolin or bentonite. It isthen advantageously accompanied by surface-active agents (at an amountof 2 to 20% by weight of the granule) of which more than half consists,for example, of at least one essentially anionic dispersing agent suchas an alkali metal or alkaline-earth metal polynaphthalene sulfonate oran alkali metal or alkaline-earth metal lignosulfonate, the remainderconsisting of nonionic or anionic wetting agents such as an alkali metalor alkaline-earth metal alkylnaphthalene sulfonate.

Moreover, although this is not indispensable, it is possible to addother adjuvants such as anti-foaming agents.

The granule according to the invention can be prepared by mixing therequired ingredients and then granulating according to severaltechniques known per se (pelletizer, fluid bed, atomizer, extrusion, andthe like). Generally, the preparation is completed by crushing followedby sieving to the particle size chosen within the above-mentionedlimits. It is alternatively possible to use granules obtained as aboveand then impregnated with a composition containing the active material.

Preferably, it is obtained by extrusion, the preparation being carriedout as shown in the Examples below.

EXAMPLE DG1

This is an example of the preparation of dispersible granules.

90% by weight of active material and 10% of urea in the pearl form aremixed in a mixer. The mixture is then milled in a pin mill or toothedroll crusher. A powder is obtained which is moistened with approximately8% by weight of water. The damp powder is extruded in aperforated-cylinder extruder. A granule is obtained which is dried andthen crushed and sieved so as to retain only the granules with a sizebetween 150 and 2,000 microns, respectively.

EXAMPLE DG2

This is another example of the preparation of dispersible granules.

The following constituents are mixed in a mixer:

    ______________________________________                                        active material          75%                                                    wetting agent (sodium alkylnaphthalene 2%                                     sulfonate)                                                                    dispersing agent (sodium 8%                                                   polynaphthalene sulfonate)                                                    water-insoluble inert filler (kaolin) 15%                                   ______________________________________                                    

This mixture is granulated in a fluid bed, in the presence of water, andis then dried, crushed and sieved so as to produce granules of between0.15 and 0.80 mm in size.

These granules can be used alone or in solution or dispersion in waterso as to produce the required dose. They can also be used to preparecombinations with other active materials, especially fungicides, thelatter being in the form of wettable powders or of granules or aqueoussuspensions.

As regards the compositions which are suitable for storing andtransporting, they more advantageously contain from 0.5 to 95% (byweight) of active substance in the case of compounds of formulae (I) and(I") and from 0.05 to 95% (by weight) of active substance in the case ofcompounds of formulae (I'') and (I").

Another subject of the invention is a process for the treatment of cropsaffected by or capable of being affected by fungal diseases,characterized in that an effective amount of a compound of formulae (I),(I') or (I") or an optically active compound of formula (I'") is appliedpreventatively or curatively to the plants or their growth site. As withthe fungicidal compositions of the invention, when the active materialis a compound of formula (I'"), it is preferable in use that thecompound be the optically pure enantiomer which has the greaterfungicidal activity of the pair or that the compound of formula (I'")contain in greatly enriched form the enantiomer having the greaterfungicidal activity of the pair.

The compounds o formulae (I), (I'), (I") and (I'") are advantageouslyapplied at doses of 0.005 to 5 kg/ha. and more specifically of 0.01 to 1kg/ha.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciated that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A compound having the formula: ##STR86## or anagriculturally acceptable salt thereof, wherein: R₁₁ is aryl orheteroaryl having 1 or 2 rings and from 5 to 10 ring atoms, from 0 to 3of the ring atoms being heteroatoms, which are the same or different,selected from the group consisting of N, O and S, at least one ringbeing aromatic or heteroaromatic, said aryl or heteroaryl beingunsubstituted or being substituted by from 1 to 3 R₆₁ substituents whichare the same or different;R₂₁ is alkyl or haloalkyl having from 1 to 3carbon atoms, said haloalkyl having 1 or more halogen atoms assubstituents; or R₁₁ and R₂₁ from, together with the ring carbon atom towhich they are bonded, a carbocyclic or heterocyclic ring having from 5to 7 ring atoms and from 0 to 3 hetero ring atoms, which are the same ordifferent, selected from the group consisting of N, O and S; or acarbocyclic or heterocyclic ring having from 5 to 7 ring atoms and from0 to 3 hetero ring atoms, which are the same or different, selected fromthe group consisting of N, O and S, which ring is fused to a benzenering; the ring system formed by R₁₁ and R₂₁ being unsubstituted or beingsubstituted by from 1 to 3 R₆₁ substituents which are the same ordifferent; R₃₁ is an alkyl or haloalkyl having from 1 to 3 carbon atoms,said haloalkyl having 1 or more halogen atoms as substituents; R₄₁ isaryl or heteroaryl having 1 to 2 rings and from 5 to 10 ring atoms, from0 to 3 of the ring atoms being heteroatoms, which can be the same ordifferent, selected from the group consisting of N, O and S, at leastone ring being aromatic or heteroaromatic, said aryl or heteroaryl beingunsubstituted or being substituted by from 1 to 3 R₆₁ substituents whichare the same or different; R₅₁ is hydrogen, formyl, acyl having from 2to 6 carbon atoms, aroyl, alkoxycarbonyl having from 2 to 6 carbonatoms, aryloxycarbonyl, alkylsulfonyl or arylsulfonyl, the aryl portionof the aroyl, aryloxycarbonyl and arylsulfonyl radicals having from 6 to10 carbon atoms and being unsubstituted or being substituted by from 1to 3 R₆₁ substituents which are the same or different; and R₆₁ ishalogenalkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy,alkylthio, haloalkylthio, cyanoalkylthio or alkylsulfonyl having from 1to 6 carbon atoms, said haloalkyl, haloalkoxy and haloalkoxythio having1 or more halogen atoms as substituents; cycloalkyl, halocyclalkyl,alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthiohaving from 3 to 6 carbon atoms, said halocyclalkyl having 1 or morehalogen atoms as substituents; nitro, cyano or thiocyanato; amino, whichis unsubstituted or is substituted by 1 or 2 substituents selected fromthe group consisting of alkyl and acyl having from 1 to 6 carbon atomsand alkoxycarbonyl having from 2 to 6 carbon atoms; or phenyl, phenoxy,phenylthio, phenylsulfonyl or pyridyloxy, each of which is unsubstitutedor is substituted by one or more of the following: halogen; alkyl,haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio oralkylsulfonyl having from 1 to 6 carbon atoms, said haloalkyl,haloalkoxy and haloalkoxythio having 1 or more halogen atoms atsubstituents; cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy,alkynyloxy, alkenylthio or alkynylthio having from 3 to 6 carbon atoms,said halocycloalkyl having 1 or more halogen atoms as substituents;nitro, cyano or thiocyanato; amino, which is unsubstituted or issubstituted by 1 or 2 substituents selected from the group consisting ofalkyl and acyl having from 1 to 6 carbon atoms and alkoxycarbonyl havingfrom 2 to 6 carbon atoms; or phenyl, phenoxy, phenylthio, phenylsulfonylor pyridyloxy.
 2. A compound according to claim 1, wherein R₁₁ isphenyl, naphthyl, thienyl, furyl, pyridyl, benzothienyl, benzofuryl,quinolinyl, isoquinolinyl or methylenedioxyphenyl, each of which isunsubstituted or is substituted by from 1 to 3 R₆₁ substituents whichare the same or different.
 3. A compound according to claim 1, whereinR₄₁ is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,benzothienyl, benzofuryl, quinolinyl, isoquinolinyl ormethylenedioxyphenyl, each of which is unsubstituted or is substitutedby from 1 to 3 R₆₁ substituents which are the same or different.
 4. Acompound according to claim 1, having the formula ##STR87## wherein R₂₁,R₃₁, R₄₁, R₅₁ and R₆₁ are as defined in claim 1, and n" is 0, 1, 2 or 3,or an agriculturally acceptable salt thereof.
 5. A compound according toclaim 4, wherein R₄₁ is phenyl, naphthyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolinyl,isoquinolinyl or methylenedioxyphenyl, each of which is unsubstituted oris substituted by from 1 to 3 R₆₁ substituents which are the same ordifferent.
 6. A compound according to claim 1, wherein R₄₁ is phenylwhich is unsubstituted or is substituted by from 1 to 3 R₆₁ substituentswhich are the same or different, or pyridyl which is unsubstituted or issubstituted by from 1 to 3 R₆₁ substituents which are the same ordifferent.
 7. A compound according to claim 2, wherein R₄₁ is phenylwhich is unsubstituted or is substituted by from 1 to 3 R₆₁ substituentswhich are the same or different, or pyridyl which is unsubstituted or issubstituted by from 1 to 3 R₆₁ substituents which are the same ordifferent.
 8. A compound according to claim 5, wherein R₄₁ is phenylwhich is unsubstituted or is substituted by from 1 to 5 R₆₁ substituentswhich are the same or different, or pyridyl which is unsubstituted or issubstituted by from 1 to 3 R₆₁ substituents which are the same ordifferent.
 9. A compound according to claim 1, wherein R₅₁ is hydrogenor acyl.
 10. A compound according to claim 4, wherein R₅₁ is hydrogen oracyl.
 11. A compound according to claim 8, wherein R₅₁ is hydrogen oracyl.
 12. A compound according to claim 4, wherein n" is 0 or wherein(R₆₁)_(n) " represents from 1 to 3 R₆₁ substituents independentlyselected from the group consisting of halogen, alkyl, alkoxy, phenoxy,halogen-substituted phenoxy and nitro.
 13. A compound according to claim12, wherein R₄₁ is phenyl which is unsubstituted or is substituted byfrom 1 to 3 R₆₁ substituents which are the same or different, or pyridylwhich is unsubstituted or is substituted by from 1 to 3 R₆₁ substituentswhich are the same or different.
 14. A compound according to claim 13,wherein R₄₁ is phenyl; phenyl having from 1 to 3 substituentsindependently selected from the group consisting of halogen, alkyl andphenoxy; pyridyl; or pyridyl having from 1 to 3 substituentsindependently selected from the group consisting of halogen and alkyl.15. A compound according to claim 14, wherein R₅₁ is hydrogen or acyl.16. A compound according to claim 1, wherein R₃₁ is alkyl having from 1to 3 carbon atoms.
 17. A compound according to claim 4, wherein R₃₁ isalkyl having from 1 to 3 carbon atoms.
 18. A compound according to claim15, wherein R₃₁ is alkyl having from 1 to 3 carbon atoms.
 19. A compoundaccording to claim 18, wherein R₃₁ is methyl.
 20. The compound accordingto claim 19, having the formula: ##STR88## wherein: n is zero and R₄₁ isphenyl;(R₆₁)_(n) is 4-chloro and R₄₁ is phenyl; n is zero and R₄₁ is2-methylphenyl; (R₆₁)_(n) is 4-chloro and R₄₁ is 2-pyridyl; n is zeroand R₄₁ is 2-chlorophenyl; n is zero and R₄₁ is 4-chlorophenyl;(R₆₁)_(n) is 3,4-dimethoxy and R₄₁ is phenyl; (R₆₁)_(n) is 4-chloro andR₄₁ is 4-chlorophenyl; (R₆₁)_(n) is 4-chloro and R₄₁ is 4-fluorophenyl;(R₆₁)_(n) is 4-chloro and R₄₁ is 2-chlorophenyl; (R₆₁)_(n) is 4-chloroand R₄₁ is 3-chlorophenyl; (R₆₁)_(n) is 4-chloro and R₄₁ is3-methylphenyl; (R₆₁)_(n) is 4-chloro and R₄₁ is 3-methylphenyl;(R₆₁)_(n) is 4-methyl and R₄₁ is phenyl; (R₆₁)_(n) is 4-fluoro and R₄₁is phenyl; (R₆₁)_(n) is 4-chloro and R₄₁ is 2-methylphenyl; (R₆₁)_(n) is4-fluoro and R₄₁ is 3-methylphenyl; (R₆₁)_(n) is 4-fluoro and R₄₁ is2-methylphenyl; (R₆₁)_(n) is 4-methyl and R₄₁ is 4-chlorophenyl;(R₆₁)_(n) is 4-methyl and R₄₁ is 3-chlorophenyl; (R₆₁)_(n) is 4-methyland R₄₁ is 2-chlorophenyl; (R₆₁)_(n) is 4-methyl and R₄₁ is4-fluorophenyl; (R₆₁)_(n) is 4-fluoro and R₄₁ is 3-chlorophenyl;(R₆₁)_(n) is 4-methyl and R₄₁ is 4-methylphenyl; (R₆₁)_(n) is 4-fluoroand R₄₁ is 4-methylphenyl; (R₆₁)_(n) is 4-methyl and R₄₁ is2-methylphenyl; n is zero and R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is4-methyl and R₄₁ is 3-methylphenyl; (R₆₁)_(n) is 4-phenoxy and R₄₁ is2-methylphenyl; (R₆₁)_(n) is 4-fluoro and R₄₁ is 4-chlorophenyl; n iszero and R₄₁ is 4-fluorophenyl; n is zero and R₄₁ is 2,4-difluorophenyl;n is zero and R₄₁ is 4-methylphenyl; (R₆₁)_(n) is 4-fluoro and R₄₁ is2-fluorophenyl; (R₆₁)_(n) is 4-methyl and R₄₁ is 2-fluorophenyl;(R₆₁)_(n) is 4-chloro and R₄₁ is 2-fluorophenyl; (R₆₁)_(n) is 4-fluoroand R₄₁ is 2-chlorophenyl; n is zero and R₄₁ is 2,3-dimethylphenyl; n iszero and R₄₁ is 3-chloro-2-pyridyl; n is zero and R₄₁ is 3-methylphenyl;n is zero and R₄₁ is 2-fluorophenyl; n is zero and R₄₁ is3-chlorophenyl; (R₆₁)_(n) is 4-fluoro and R₄₁ is 3-methyl-2-pyridyl;(R₆₁)_(n) is 4-fluoro and R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is 4-chloroand R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is 3-chloro and R₄₁ is phenyl;(R₆₁)_(n) is 3-chloro and R₄₁ is 3-methylphenyl; (R₆₁)_(n) is 3-chloroand R₄₁ is 3-chlorophenyl; (R₆₁)_(n) is 3-chloro and R₄₁ is3-fluorophenyl; (R₆₁)_(n) is 3-chloro and R₄₁ is 2-methylphenyl;(R₆₁)_(n) is 3-chloro and R₄₁ is phenyl; (R₆₁)_(n) is 3-fluoro and R₄₁is 3-fluorophenyl; (R₆₁)_(n) is 3-fluoro and R₄₁ is 3-chlorophenyl;(R₆₁)_(n) is 3-methyl and R₄₁ is phenyl; (R₆₁)_(n) is 3-methyl and R₄₁is 3-fluorophenyl; (R₆₁)_(n) is 4-phenoxy and R₄₁ is 2-pyridyl;(R₆₁)_(n) is 2,4-difluoro and R₄₁ is phenyl; (R₆₁)_(n) is 2,4-difluoroand R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is 4-phenoxy and R₄₁ is phenyl;(R₆₁)_(n) is 4-phenoxy and R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is 2-chloroand R₄₁ is phenyl; n is zero and R₄₁ is 4-phenoxyphenyl; (R₆₁)_(n) is2-chloro and R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is 2-fluoro and R₄₁ isphenyl; (R₆₁)_(n) is 2-fluoro and R₄₁ is 3-fluorophenyl; (R₆₁)_(n) is2,4-difluoro and R₄₁ is 3-chlorophenyl; (R₆₁)_(n) is 2-fluoro and R₄₁ is3-chlorophenyl; (R₆₁)_(n) is 4-isopropyl and R₄₁ is phenyl; (R₆₁)_(n) is4-phenoxy and R₄₁ is 3-methyl-2-pyridyl; (R₆₁)_(n) is 4-isopropyl andR₄₁ is 3-fluorophenyl; (R₆₁)_(n) is 3-methyl and R₄₁ is 3-chlorophenyl;(R₆₁)_(n) is 4-isopropyl and R₄₁ is 3-chlorophenyl; (R₆₁)_(n) is 4-bromoand R₄₁ is phenyl; (R₆₁)_(n) is 4-nitro and R₄₁ is phenyl; (R₆₁)_(n) is3-phenoxy and R₄₁ is phenyl; (R₆₁)_(n) is 2,4-difluoro-4-phenoxy and R₄₁is 3-fluorophenyl; (R₆₁)_(n) is 2,4-difluoro-4-phenoxy and R₄₁ isphenyl; or (R₆₁)_(n) is 4-fluoro-4-phenoxy and R₄₁ is phenyl.
 21. Thecompound according to claim 1, having the formula: ##STR89##
 22. Afungicidal composition comprising: (a) a fungicidally effective amountof a compound of formula (I") according to claim 1, or an agriculturallyacceptable salt thereof; and(b) at least one member selected from thegroup consisting of an agriculturally acceptable solid or liquid vehicleand an agriculturally acceptable surface-active agent.
 23. A fungicidalcomposition comprising:(a) a fungicidally effective amount of a compoundof formula (I"a) according to claim 4, or an agriculturally acceptablesalt thereof; and (b) at least one member selected from the groupconsisting of an agriculturally acceptable solid or liquid vehicle andan agriculturally acceptable surface-active agent.
 24. A fungicidalcomposition comprising:(a) a fungicidally effective amount of a compoundof formula (I"a) according to claim 5, or an agriculturally acceptablesalt thereof; and (b) at least one member selected from the groupconsisting of an agriculturally acceptable solid or liquid vehicle andan agriculturally acceptable surface-active agent.
 25. A fungicidalcomposition according to claim 22, comprising from about 0.5% to about95% by weight of compound of formula (I").
 26. A fungicidal compositionaccording to claim 23, comprising from about 0.5% to about 95% by weightof compound of formula (I"a).
 27. A method for the treatment orprevention of fungal disease in crops, said method comprising applyingto said crops or to the area in which they grow a fungicidally effectiveamount of a compound of formula (I") as claimed in claim 1, or anagriculturally acceptable salt thereof.
 28. A method for the treatmentor prevention of fungal disease in crops, said method comprisingapplying to said crops or to the area in which they grow a fungidicallyeffective amount of a compound of formula (I"a) according to claim 4, oran agriculturally acceptable salt thereof.
 29. A method for thetreatment or prevention of fungal disease in crops, said methodcomprising applying to said crops or to the area in which they grow afungidically effective amount of a compound of formula (I"a) accordingto claim 5, or an agriculturally acceptable salt thereof.
 30. A methodaccording to claim 27, wherein from about 0.0005 to about 5 kg/ha ofcompound of formula (I") is applied.
 31. A method according to claim 30,wherein from about 0.01 to about 1 kg/ha of compound of formula (I") isapplied.
 32. A method according to claim 28, wherein from about 0.0005to about 5 kg/ha of compound of formula (I"a) is applied.
 33. The methodaccording to claim 32, wherein from about 0.01 to about 1 kg/ha ofcompound of formula (I"a) is applied.
 34. A method for the treatment orprevention of fungal disease in crops, said method comprising applyingto said crops or to the area in which they grow a fungidically effectiveamount of a composition according to claim
 22. 35. A method for thetreatment or prevention of fungal disease in crops, said methodcomprising applying to said crops or to the area in which they grow afungidically effective amount of a composition according to claim 23.36. A method for the treatment or prevention of fungal disease in crops,said method comprising applying to said crops or to the area in whichthey grow a fungidically effective amount of a composition according toclaim 24.